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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Zeitschrift für Lebensmittel-Untersuchung und -Forschung 208 (1999), S. 183-188 
    ISSN: 1431-4630
    Keywords: Key words Sulphadimidine ; Fermented sausage ; Carbon-14-labelling ; Rat ; Bound residues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract  Sulphadimidine (SDM), a drug frequently administered to pigs, is partially converted into other compounds by processing meat to produce raw, fermented sausage. With the aid of 14C-labelled SDM, evidence was obtained that part of the radioactive matter was covalently bound to the matrix. Part of these bound residues could be released in vitro by 4 M HCl at 21  °C or by 0.024 M HCl at 37  °C. Female rats were also able to release bound SDM residues and to excrete these in their urine, in amounts approaching those obtained by treatment with 4 M HCl. Both the parent compound and its main metabolite, N 4-acetyl-SDM, were observed in the urine of rats.
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  • 2
    ISSN: 1432-0568
    Keywords: Key words Morphogenesis ; Histochemistry ; Lectins ; Carbohydrates ; Salivary glands ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The developmental expression of salivary glycoconjugates was investigated in the rat submandibular and sublingual glands by conventional and lectin histochemistry. By the time of the first differentiation of secretory structures, in spite of similar morphological features, a different histochemical reactivity was detected, accounting for a relevant content of neutral glycoconjugates in the submandibular gland and the occurrence of both neutral and acidic glycoconjugates in the sublingual one. The use of lectins allowed the main changes of secretory components to be noted around gestational day 18. DBA and WGA lectins seemed to act as pre- and post-natal development markers while Con A lectin was indicative of post-natal differentiation. Taken together, data from lectin histochemistry indicated the transitional occurrence of glycoconjugates, probably involved in temporally restricted functions, as well as the co-existence of different secretory components that might also reflect maturational changes of single products.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 200 (1999), S. 521-531 
    ISSN: 1432-0568
    Keywords: Key words Development ; Internal capsule ; Nucleus basalis ; Rat ; Thalamus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This study defines several features of the early connections of the developmentally transient perireticular thalamic nucleus of rats. The neocortex of developing rats was injected with either DiI, biotinylated dextran, WGA-HRP (wheatgerm agglutinin conjugated-horseradish peroxidase), fluorescent latex beads or cholera toxin subunit B (CTB) and their brains were processed for tracer detection with standard methods. In general, tracer injections into various regions of the developing neocortex revealed no labelled neurones within the perireticular nucleus, although some of these tracers (WGA-HRP, dextran) labelled many of the amoeboid microglial cells that are found within this nucleus. There were, however, many retrogradely labelled neurones in a region adjacent to the perireticular nucleus, within the nucleus basalis of the basal forebrain (medial edge of globus pallidus). Their identity was confirmed as neurones of the nucleus basalis since they were all were similar in morphology and somal size to neurones that were immunoreactive to NGFr (nerve growth factor receptor), an antigen found only among neurones of the nucleus basalis and basal forebrain. Moreover, double labelling experiments revealed that most, if not all, of the cortically labelled neurones were NGFr-immunoreactive also. Thus, in conclusion, our results suggest that the perireticular nucleus does not project to the neocortex; the only neurones in the general vicinity of the perireticular nucleus that have a cortical projection form part of the nucleus basalis.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 200 (1999), S. 533-540 
    ISSN: 1432-0568
    Keywords: Key words Coronary vasculogenesis ; Angiogenesis ; Coronary artery ; Development ; Rat ; Embryonic heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this work was to address spatiotemporal and morphologic patterns of coronary artery development in rats, based on immunohistochemical and ultrastructural studies of hearts at different stages of prenatal development. Griffonia simplicifolia I lectin and α-smooth muscle antibody were used to demonstrate endothelial cells and/or their precursors and smooth muscle cells, respectively. Ultrastructural examination was performed on ED14–16 hearts to study the morphology of the developing coronary arteries in different regions of the truncus arteriosus and adjacent myocardium. On ED14 endothelial-like cells present within the mesenchyme surrounding the outflow tract penetrated the aortic wall and the truncoconal proximal myocardium. On ED15 these penetrating cells formed vascular clusters, which were the first signs of presumptive vascular channels. Development of the coronary artery proceeded by coalescence of discontinous vascular clusters, formation of the lumen (vascular channels) and establishing a connection of the proximal part with the aorta. The second layer of cells around vascular channels (embryonic media) consisted of mesenchymal cells that were attracted to the immature vessel and were first seen on ED15. At this time no lumenized connection of the coronary artery with the aorta has been seen. After the lumenized connection of the coronary artery with the aorta had been established perivascular cells of the media started to differentiate into vascular smooth muscle, as was shown by α-smooth muscle actin-staining. Further development and differentiation of the media and adventitia proceeded distally (towards the apex).
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 199 (1999), S. 265-280 
    ISSN: 1432-0568
    Keywords: Key words Cat ; Rat ; Immunocytochemistry ; NADPH-diaphorase ; Thalamus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To gain insight into the cellular organisation of the zona incerta, we have examined the chemoarchitectonic properties of this ”uncertain zone”. The brains of Sprague-Dawley rats and common cats were processed for immunocytochemistry or NADPH-diaphorase histochemistry using standard methods. For the immunocytochemistry, antibodies to γ-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD), parvalbumin, calbindin, tyrosine hydroxylase, somatostatin, serotonin and glutamate were used. Two general patterns of distribution in the zona incerta were seen. First, labelled cells were restricted largely to one of the cytoarchitectonically defined sectors of the zona incerta. For instance, GABA, GAD and parvalbumin-immunoreactive cells were found principally within the ventral sector, NADPH-diaphorase and glutamate-immunoreactive cells within the dorsal sector and tyrosine hydroxylase- and somatostatin-immunoreactive cells within the rostral sector. Second, labelled cells were scattered somewhat across all incertal sectors, with no clear region of concentration. This pattern included the calbindin- and serotonin-immunoreactive cell groups. These results indicate that the zona incerta is made up of many neurochemically distinct cell groups, some of which respect the well-defined cytoarchitectonic boundaries of the nucleus, whilst others do not. This rich neurochemical diversity in the zona incerta suggests that this nucleus may have differential effects on the different structures that it projects to.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 200 (1999), S. 413-417 
    ISSN: 1432-0568
    Keywords: Key words Receptor cell ; Axon ; Vomeronasal organ ; Regeneration ; Rat ; HRP-WGA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Chemosensory neurons in the vomeronasal epithelium (vomeronasal neurons) regenerate following experimentally induced degeneration. Transection of the vomeronasal nerves leads to retrograde degeneration of vomeronasal neurons followed by replacement of the cell population. The projection of the axons of regenerated vomeronasal neurons was examined by horseradish peroxidase(HRP) histochemistry and electron microscopy. HRP-wheat germ agglutinin (WGA) was placed on the surface of the vomeronasal organ of the rat. Dense distribution of HRP-labeled fibers was observed in the vomeronasal nerve and glomerular layers in the accessory olfactory bulb (AOB) of the intact rat. At one week after transection, HRP-labeled fibers were not found in the AOB, and no labeled fibers could be observed on the medial surface of the olfactory bulb where the vomeronasal nerve traversed. Three weeks after transection, labeled fiber bundles were observed on the medial surface of the olfactory bulb in all animals. No labeled fibers were detected in the AOB. From 12 to 32 weeks after transection, projection of HRP-labeled fibers was identified in the AOB in 8 out of 26 rats (the incidence of projection was 30%). But the number of projection fibers on the operated side was much smaller than on the control side. Electron microscopy confirmed that the HRP-labeled terminals make synaptic contacts with neurons in the AOB.
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  • 7
    ISSN: 1432-1831
    Keywords: Key wordsToxoplasma gondii ; Toxoplasmosis ; Rat ; Animal model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of γδ T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of γδ T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.
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  • 8
    ISSN: 1432-1211
    Keywords: Key words Class II MHC sequence ; Rat ; Cloning ; RT-PCR ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0738
    Keywords: Key words Benzene ; Benzene metabolites ; Diabetes ; Cytochrome P-450 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Benzene is a ubiquitous environmental pollutant primarily metabolized by a cytochrome P-450 (CYP-450) isoenzyme, CYP-450 IIE1. A consistent induction of CYP450 IIE1 has been observed in both rat and human affected by diabetes mellitus. The aim of this study was to evaluate whether streptozotocin (STZ)-induced diabetes determines modifications in the metabolic pathways of benzene in rat. Benzene (100 mg/kg per day, dissolved in corn oil) was administered i.p. once a day for 5 days. Urine samples were collected every day in STZ-treated and normoglycaemic animals, treated and untreated with benzene (n = 10). Urinary levels of trans,trans-muconic acid and of phenol, catechol and hydroquinone (free and conjugated with sulphuryl and glucuronic group) were measured by high-performance liquid chromatography (HPLC). In normoglycaemic rats during the 5 days of treatment with benzene we observed a progressive and significant decrement in the urinary excretion of phenol, phenyl sulphate and glucuronide, catechol, catechol glucuronide, hydroquinone, hydroquinone glucuronide and t,t-muconic acid (P 〈 0.05). In the diabetic animals, conversely, the same metabolites showed progressively increasing urinary levels (P 〈 0.05). Catechol sulphate and hydroquinone sulphate levels were below the instrument's detection limit. In the comparison between diabetic and normoglycaemic benzene treated rats, the inter-group difference was significant (P 〈 0.05) from day 3 of treatment for t,t-muconic acid, and from day 1 for free and conjugated phenol, free and glucuronide catechol and free hydroquinone. In the normoglycaemic rat exposed to benzene the decreasing trend observed in urinary excretion of free and conjugated metabolites may be due to their capability to reduce cytochromial activity. Conversely, in the diabetic rat, urinary levels of benzene metabolites tended to increase progressively, probably due to the consistent induction of CYP-450 IIE1 observed in diabetes, which would overwhelm the inhibition of this isoenzyme caused by phenolic metabolites. Furthermore, the metabolic switch towards detoxification metabolites observed after administration of high doses of benzene is not allowed in the diabetic because of reduced glutathione-S-transferase activity. As a consequence, higher levels of hydroquinone, phenol and catechol, considered the actual metabolites responsibles for benzene toxicity, will accumulate in the diabetic rat. Extrapolating these data to human, we may thus suggest that occupational exposure to benzene of a diabetic subject poses a higher risk level, as his metabolism tends to produce and accumulate higher levels of reactive benzene catabolites.
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  • 10
    ISSN: 1432-1106
    Keywords: Key words Spatial function ; Water maze ; Procedural learning ; Cerebellum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Recently, we demonstrated the prevalent role of cerebellar networks in the acquisition of the procedural components of spatial information by testing hemicerebellectomized (HCbed) rats in a classical spatial task, the Morris water maze (MWM). As procedures used in the water maze are a mixture of different components (that is, general procedures, exploration procedures, direct reaching procedures), for optimally solving a spatial task all procedural components must be opportunely managed. Thus, severely impaired procedural learning of cerebellar origin can be better comprehended by fractionating the procedural facets. To this aim, a two-step water-maze paradigm was employed. Normal rats were first trained to search for a hidden platform moved to a different position in each trial, utilizing a water maze setting in which visual cues were abolished by heavy black curtains surrounding the tank. In this paradigm, normal animals solved the task by using general and exploration procedures, but they could not use direct reaching skills. A subgroup of these pretrained animals was then HCbed and, after recovery from cerebellar lesion, was tested in a water maze with normal environmental cues available, a paradigm in which normal animals develop abilities for reaching the target with very direct trajectories. Pretrained HCbed animals, however, did not display the typical spatial deficits of naive HCbed rats, persisted in exhibiting the scanning strategy learned during pretraining, and never displayed direct reaching skills. In conclusion, cerebellar networks appear to be involved in the acquisition of all procedural facets necessary for shifting behavior within the maze until direct reaching of the platform. The lack of flexibility in changing exploration strategies displayed by pretrained HCbed rats is interpreted by taking into account the well-known cerebellar frontal interplay sculpting a specific cerebellar role in the acquisition of spatial procedural steps.
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  • 11
    ISSN: 1432-1106
    Keywords: Key words Acetylcholine ; Brain slices ; Cerebral cortex ; Long-term depression ; Rat ; Synaptic plasticity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The ability of layer I activation to facilitate the induction of long-term potentiation (LTP) in layer II/III horizontal connections of motor cortex (MI) was examined in rat brain slice preparations. Field potentials evoked in layer I and layer II/III horizontal pathways were recorded from radially aligned MI sites. While theta burst stimulation (TBS) of layer II/III pathways alone failed to induce LTP, simultaneous TBS of layer I and layer II/III inputs on alternate sides of the recording electrodes induced LTP in the layer II/III input in 8 out of 13 slices (mean change +20±6%; N=13). In the same cases, the layer I connections showed mixed effects: LTP in three cases, LTD in five cases, and no modification in five slices. Despite the facilitatory effect of layer I activation on layer II/III LTP induction, we found that the critical circuitry for this effect was outside layer I. Cutting the layer I fibers selectively in the slice did not prevent layer II/III LTP induction, while cuts preserving only layer I blocked layer II/III LTP after conjoint I+II/III TBS. Cholinergic fibers were evaluated as candidates for the facilitatory effect because they branch widely in both layers and they are thought to participate in synaptic modification. The cholinergic contribution to layer II/III LTP facilitation was investigated using bath application of muscarinic antagonists. Muscarinic blockade prevented facilitation of layer II/III LTP by layer I coactivation. Instead, conjoint stimulation in 10 µM atropine produced long-term depression (LTD) of layer II/III (–18±9%; N=11) as well as of layer I (–21±6%; N=11) horizontal responses. These results indicate that connections formed within layer I are ineffective in promoting LTP in the deeper-lying horizontal connections; the critical route by which layer I stimulation influenced LTP induction required the circuitry in the deeper layers, particularly the cholinergic system. Thus, it appears that diffuse cholinergic afferents provide an additional route to regulate activity-dependent synaptic modificaton in horizontal cortical connections.
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  • 12
    ISSN: 1432-1106
    Keywords: Key words Motor unit ; Contraction ; Stimulation pattern ; Rat ; Medial gastrocnemius
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of irregularity in the pattern of stimulation on the tension produced by motor units in the rat medial gastrocnemius muscle were investigated. The effects of decreasing as well as increasing the interpulse intervals were observed for each motor unit in tetani fused to different degrees. For each motor-unit type, it was found that the effects of these changes depended on the extent of tetanic fusion. Decreasing the interpulse interval produced an increase in tension during the tetanus: the more fused the profile of tetanus, the smaller the tension increase. Increasing the interpulse interval resulted in a decrease in tetanic tension. This effect was most prominent when the tetanic fusion index was approximately 0.75. This phenomenon resulted from the prolongation in relaxation when tetanic fusion increased, thereby preventing a decrease in tension when the interpulse interval increased. We also investigated the effects of introducing a short interpulse interval (”doublet”) at the beginning of the stimulation. The doublets produced increased tetanic tension with a more fused profile. However, the doublet enhanced the sensitivity of the tetanus to increases in interpulse interval and decreased its sensitivity to decreases in interpulse intervals. Slow-twitch motor units appeared to be significantly less sensitive to both increases and decreases in interpulse interval than fast-twitch units. This suggests that slow-twitch units are better suited for producing long-lasting contractions with a constant tension level. Conversely, the high sensibility of fast-twitch units to changes in stimulation frequency enhances their participation in regulation of tension of the muscular contraction.
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  • 13
    ISSN: 1432-1106
    Keywords: Key words Thyroid hormone ; RT-PCR ; p75 receptor ; trkA ; trkB ; trkC ; Septum ; Hippocampus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Early postnatal application of thyroid hormones to rats results in morphological changes of the septo-hippocampal cholinergic and the hippocampal mossy fiber systems. Modulation in the expression of either neurotrophins and/or their receptors is postulated to be involved in these effects. In a recent study, we showed that, after thyroxine application, the mRNA expression of neurotrophins of the nerve-growth-factor (NGF) family is significantly upregulated both in septum and hippocampus. To test whether the neurotrophin receptors (the low-affinity neurotrophin receptor p75 and the specific high-affinity receptors trkA, trkB, and trkC) were also affected by hormone administration, newborn rats were treated daily with subcutaneous injections of thyroxine until postnatal day 12 (P12) at latest. Control animals received corresponding injections of saline. The pups were sacrificed at defined intervals from P9 to P14. The septal areas and the hippocampi were analyzed using the reverse-transcription polymerase chain reaction (RT-PCR) method for quantification of p75, trkA, trkB, and trkC mRNA levels. Analysis of variance over the total investigation period revealed no significant general increases of the gene expressions of either neurotrophin receptor, neither in the septum nor in the hippocampus, although previous results have shown marked changes in neurotrophin levels. On particular postnatal days, significant upregulation could be observed in hippocampus for trkB and trkC. From these and recent data, we conclude that modulation of neurotrophin expression rather than neurotrophin-receptor expression contributes to the morphological modifications within the hippocampal mossy fiber system and the septo-hippocampal cholinergic system.
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  • 14
    ISSN: 1432-1106
    Keywords: Key words Focal cerebral ischemia ; Photothrombosis ; Reperfusion ; Spontaneous recanalization ; Cerebral blood flow ; Edema ; Penumbra ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In clinical thromboembolic stroke, spontaneous late recanalization is a common feature, but one which has been very sparsely studied experimentally. This study aimed at enabling the study of spontaneous reperfusion and exploring its consequences by modifying a recently developed photothrombotic-stroke model that focuses on the region-at-risk located within an ischemic ring-locus. The exposed crania of male Wistar rats (280–340 g) were subjected to a ring-shaped (5.0 mm outer diameter and 0.35 mm thick) laser-irradiation beam (514.5 nm; 0.89 W/cm2) for 2 min simultaneously with intravenous erythrosin B (17 mg/kg) infusion for 30 s. Transcardial carbon-black perfusion experiments revealed a ring-shaped cortical perfusion deficit at 4 h post-irradiation, which progressively increased at 10, 24, and 48 h, at which time the whole region-at-risk was pale with single distal branches of the middle cerebral artery being extensively narrowed, but not occluded. At 72 h, spontaneous reperfusion was observed in the region-at risk, which was even more pronounced at 7 and 28 days. Cortical cerebral blood flow (cCBF), measured by laser-Doppler flowmetry, was distinctly reduced at 2 min post-irradiation and further decreased slightly during 4 h of recording to ca. 24% of baseline values at the ring locus and 40% in the region-at-risk. In the region-at-risk, cCBF flow values were 23–30% of the baseline at 24–48 h post-irradiation, followed by a relative cCBF increase to 71 and 77% at 72 and 96 h post-irradiation. Brain water content in the ischemic part of the cortex increased steadily from 4 to 48 h post-irradiation; at 72 h, it leveled off and returned to control values at 7 days. In conclusion, by employing a laser beam in the shape of a thin ring, critically sustained cCBF reduction was followed by late, consistent spontaneous reperfusion in the region-at-risk in this novel photochemically induced stroke-in-evolution model.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 126 (1999), S. 307-314 
    ISSN: 1432-1106
    Keywords: Key words Striatal dopamine depletion ; Rat ; Locomotion ; Ground reaction forces ; Gait ; Unilateral ; Kinetic ; Centre of mass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Hemi-parkinsonian rats have preserved postural reflexes but are impaired in initiation of voluntary movements. Surprisingly, these rats can walk and run, suggesting that they can access some compensatory strategy to overcome the rigidity in their impaired limbs. The purpose of the present experiment was to investigate the locomotor compensations made by hemi-parkinsonian rats by measuring the forces exerted by the limbs on the ground throughout the stride during trotting. Rats with unilateral dopamine depletion produced by injection of 6-hydroxydopamine into the nigrostriatal bundle were trained to run back and forth in an alley for food reinforcement. Ground reaction forces were measured in three orthogonal directions using a force plate embedded in the runway. Rats were also videotaped so that limb movements were synchronized with force recordings. Although locomotion was obviously impaired, the affected limbs could support weight and provide some braking forces. In addition, the impaired hindlimb provided significant propulsive force, and a relatively large laterally directed force. Analysis of vertical movement of the centre of mass suggested that the impaired hindlimb was being used partly as a spring. The most significant abnormalities were seen during the diagonal couplet of the impaired forelimb and the unimpaired hindlimb, partly reflecting the important compensatory role of the unimpaired hindlimb. These results demonstrate that this method is useful in the analysis of hemi-parkinsonian gait and provide insights as to how rats can use an impaired limb to produce weight support and propulsion.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 126 (1999), S. 351-358 
    ISSN: 1432-1106
    Keywords: Key words Tooth pulp ; Phrenic nerve ; Electrical stimulation ; C1 spinal neuron ; Digastric electromyogram ; Somatic receptive field ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Effects of electrical stimulation of the ipsilateral tooth pulp (TP) on C1 spinal neurons were determined in 33 anesthetized rats. One hundred and seven neurons responded to TP stimulation. In 10 rats, the activity of 18 C1 spinal neurons and the amplitude of a digastric electromyogram (dEMG, n=10) increased proportionally during the TP stimulation at an intensity of 1–3 times the threshold for jaw-opening reflex (JOR). Excitatory receptive somatic fields were examined in 61 neurons. Somatic field locations of many neurons (67.2%) involved the ipsilateral face, neck, and jaw. The activity of 45 neurons was increased by both noxious pinch and brushing hair. Of the 107 C1 spinal neurons responding to TP stimulation, 55 were tested to determine the effects of electrical stimulation of the ipsilateral phrenic nerve (PN) above the heart. Twenty-eight of 55 neurons tested were excited; no change in activity was seen for the remaining 27 neurons. The activity of six neurons increased as the intensity of PN stimulation was increased. Excitatory receptive somatic fields were determined in 28 neurons, and somatic field locations of 17 neurons (60.7%) included the ipsilateral face, neck, and jaw. Both noxious pinch and brushing hair excited all 28 neurons. These results suggest that there may be the convergence of face, neck, jaw, TP, and PN afferents on the same C1 spinal neurons in the rat.
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  • 17
    ISSN: 1432-1106
    Keywords: Key words Suprathreshold heat pain ; Adapting temperature ; Temporal parameters ; Spinal dorsal horn neuron ; Descending control ; Rat ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The influence of stimulus temperature rise rate (2.5ºC/s, 5.0ºC/s, and 10.0ºC/s), adapting (baseline) temperature (25ºC, 30ºC, and 35ºC), and duration of peak stimulus temperature (1.0 s, 2.5 s, 5.0 s, and 10.0 s) on responses evoked by noxious heat stimuli of suprathreshold intensity was studied in wide dynamic range (WDR) neurons of the rat spinal dorsal horn. The spinal neuronal responses were compared with human psychophysical data obtained using the same stimuli. Noxious heat stimuli with a peak temperature of 54ºC were applied with a contact thermostimulator to the glabrous skin of the hindfoot in rats or to the palmar skin in humans. With the highest ramp rate and the highest adapting temperature, the sensory and spinal neuronal response latencies were decreased more than expected on the basis of the change in physical parameters of the stimulus. The magnitudes of sensory and spinal neuronal response were independent of the stimulus ramp rate, whereas pain magnitude estimates and spinal neuronal impulse counts evoked by the same peak stimulus temperature were increased with an increase in the adapting stimulus temperature. The onset latencies of pain reactions and spinal neuronal responses were independent of the peak stimulus duration, whereas the latency of the maximum discharge in spinal neurons increased with prolongation of the peak stimulus. The sensory magnitude estimate of pain and the neuronal impulse count were increased with increase in stimulus duration. Following spinalization, the spinal neuronal responses were stronger and the stimulus duration-dependent increase in the impulse count developed faster. Moreover, the peak frequency of spinal neuronal response increased significantly with prolongation of the heat stimuli after spinalization, but not in animals with an intact spinal cord. The results indicate that stimulus rise rate, stimulus duration, and the adapting temperature are important factors in determining the sensory and spinal neuronal responses to high-intensity heat stimuli. The changes in the total impulse counts evoked by varying supraliminal heat stimuli in spinal dorsal horn WDR neurons corresponded well with the changes in pain magnitude estimates in humans. Also, the changes in spinal neuronal response onset latencies were accompanied by corresponding changes in onset latencies of human pain reactions but not with pain magnitude estimates. The effect of spinalization indicated that descending pathways control not only the response magnitude in the spinal dorsal horn WDR neurons but also the temporal characteristics of the spinal neuronal response.
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  • 18
    ISSN: 1432-1106
    Keywords: Key words Opioids ; µ-Receptors ; κ-Receptors ; Aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We studied the effects of morphine injected either systemically or into the dorsal periaqueductal gray (DPAG) or nucleus accumbens (NA) using conventional and ethological analyses of behavior of rats submitted to the elevated plus-maze test with transparent walls. Intraperitoneal morphine (0.1 mg/kg and 0.3 mg/kg) increased both standard and ethological measures, expressing general exploratory activity such as total arm entries, end-exploration, scanning, head-dipping, and rearing. Morphine 10 (7.6 µg/µl) and 30 nmol (23 µg/µl) injected into nucleus accumbens produced similar effects, which were blocked by i.p. naltrexone (2.0 mg/kg), an opioid antagonist with good affinity for µ-opioid receptors. Morphine injected into the DPAG produced either antiaversive (10 nmol) or aversive effects (30 nmol), which respectively reduced and increased entries and time spent in the open arms and behaviors associated with risk assessment (peeping out, stretched attend postures, and flat back approach). The proaversive effects were inhibited by i.p. norbinaltorphimine (2.0 mg/kg), a selective inhibitor for κ-opioid receptors. These findings support the contention that at least some of the motivational effects of morphine may be due to activation of opioid mechanisms in nucleus accumbens, and DPAG has neural substrates for antiaversive and aversive effects of morphine. Moreover, on the basis of previous and present data obtained in this laboratory, it is suggested that stimulation of µ-opioid receptors inhibits and stimulation of κ-receptors activates the neural substrate of aversion in the DPAG. On the other hand, the increase in exploratory behavior due to interaction of morphine with µ-opioid receptors in the nucleus accumbens may be due to the stimulation of the interface between neural substrates of motivation and motor output in this structure.
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  • 19
    ISSN: 1432-1106
    Keywords: Key words Learning and memory ; Electrical stimulation ; Parafascicular thalamic nucleus ; Two-way active avoidance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To evaluate whether electrical stimulation of the parafascicular nucleus (PF) can improve short-term (24 h) and/or long-term (21 days) retention of two-way active avoidance, rats were implanted with an electrode at this nucleus (experimental groups) or above it (control groups). After a single 30-trial acquisition session, experimental groups were submitted to a 10-min session of electrical stimulation. Results showed that the simple implantation of an electrode at the posterior PF enhanced by itself the acquisition of two-way active avoidance, in such a way that the subsequent stimulation of this region may have been unable to further improve the performance of the rats. On the other hand, parafascicular stimulation improved the 24-h retention of the task in a site-specific way, since this effect was mainly seen after stimulation of the central PF region. The facilitative effect on 24-h retention could also depend on the level of performance achieved during the acquisition session, because this improvement was only evidenced in poorly learning animals. No effects were found on 21-day retention. The present results confirm the involvement of the PF in learning and memory and the functional heterogeneity of this nucleus.
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  • 20
    ISSN: 1432-1106
    Keywords: Key words Coherence ; Entorhinal cortex ; Cortex ; Hippocampus ; Amygdala ; 192 IgG-saporin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 µg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%–84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin.
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  • 21
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    Experimental brain research 126 (1999), S. 501-508 
    ISSN: 1432-1106
    Keywords: Key words Spinal cord ; Wide-dynamic-range neurons ; Tail formalin ; Sciatic afferences ; Thermal stimulation ; Facilitation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A recent model of formalin injection in the tail induced a facilitation of the hindpaw withdrawal reflexes. In the present work we tried, after injecting formalin into the tail of the albino rat, to determine the spontaneous activity and response changes of lumbar sciatic wide-dynamic-range neurons to thermal stimulations of the paw at 45°C and 48°C (the respective thresholds for noxious and non-noxious thermal stimuli). The experiments were carried out with multiple recording electrodes placed in a comb array in the lumbar segments of the spinal cord at L4–L6 level in the sciatic projection field. A significant facilitation of the spontaneous activity was already evident 2 min after injection; at 5 min there were strong facilitations to the thermal stimuli. Stimuli at 45°C, often ineffective prior to the formalin injection, became strongly excitatory. Stimuli at 48°C evoked more conspicuous responses. This facilitatory effect on spontaneous and thermal responses followed a time-course comparable to that described for the excitations seen after paw formalin injection, but the duration was more prolonged, lasting more than 2 h. These data indicate a facilitatory role of the formalin effects on spinal sciatic neurons after injection in the tail. It is proposed that the mutual effects of spinal neurons in distant spinal segments could explain the facilitation and such a time-course, and that a role in the development of prolonged pain could be envisaged.
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  • 22
    ISSN: 1432-1106
    Keywords: Key words Protein lateral mobility ; Plasma membrane of brain cells ; Fluorescence recovery after photobleaching ; Concanavalin-A-receptors ; Concanavalin-A-fluorescein conjugate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A new method has been developed for ex vivo preparation of brain cortical cells of BN/BiRijHsd rats to make them suitable for the measurement of the lateral diffusion coefficient of the membrane components by means of fluorescence recovery after photobleaching (FRAP). The method involves chopping the brain cortex into pieces of less than 1 mm. These parts are stained with a fluorescent label (e.g., concanavalin-A-fluorescein, Con-A-FL conjugate) and then gently pressed onto a microscope slide using the coverslip. In the resulting specimen, the largest cells of the cortex can be recognized in phase-contrast image, sufficiently stained by the label and ready for the FRAP measurement. The lateral diffusion coefficient of Con-A-receptor proteins (D p) was measured in such brain cell preparations of 15 female rats in four age groups (5.6–31.8 months) and 11 males in three age groups (13.8–31.8 months). Highly significant negative, linear age correlation of D p (R=−0.9958 in females, and −0.9956 in males) were found, the regression equations being D p,=(8.8311–0.1425 X)−10 and D p█=(9.3240−0.1630 X)−10 cm2/s, respectively, where X is age in months. The data confirm that the lateral mobility of plasma membrane proteins represents an important biomarker of cellular aging in the brain cortical cells of BN/BiRijHsd rats.
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  • 23
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    Experimental brain research 128 (1999), S. 309-314 
    ISSN: 1432-1106
    Keywords: Key words GABA ; Bromodeoxyuridine ; Proliferation ; Immunohistochemistry ; Retina ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The birthdates of GABAergic amacrine cells in the rat retina were investigated by immunocytochemistry using anti-GABA and anti-bromodeoxyuridine (BrdU) antisera. The ratio of co-localization of GABA to BrdU increased gradually from embryonic-day 13 (E13) and showed a peak value on E18 in the central retina and on E20 in the periphery. After birth, until postnatal-day 3 (P3), a few co-localized cells were observed in the inner nuclear layer (INL). However, in the peripheral retina, co-localized cells were observed in the INL and ganglion cell layer until P5. Our results suggest that the birthdates of GABA-immunoreactive cells vary, depending on cell-type and that there is a temporal lag in the GABA-immunoreactive cell production in the peripheral retina relative to the central retina.
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  • 24
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    Pediatric surgery international 15 (1999), S. 201-205 
    ISSN: 1437-9813
    Keywords: Key words Esophagus ; Atresia ; Notochord ; Adriamycin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Esophageal atresia (EA) is often accompanied by vertebral defects and other anomalies. The adriamycin rat model of EA has disclosed the embryology of the malformation and shown that the vertebrae and notochord are also abnormal. This study describes the nature of notochord malformations in rat embryos exposed to adriamycin. Time-mated rats received either 1.75 mg/kg adriamycin or vehicle i.p. on gestational days (E) 6 to 9; E-12, E-12.5, and E-13 embryos were harvested, embedded in paraffin, and serially sectioned at 3 μm in transverse plane from the head to the stomach for subsequent PAS staining. The findings in both groups were compared at the three endpoints. Control embryos had neither tracheoesophageal nor notochord malformations. On day 12, only 11/36 adriamycin embryos were normal; 7/36 had abnormal notochords, 11/36 had EA, and 7/36 had both. The corresponding figures for 12.5 days were 12/27, 0/27, 7/27, and 8/27 and those for the day 13 7/23, 5/23, 3/23, and 8/23. The malformed notochords were thickened, bifurcated, or trifurcated in the sagittal plane. The simultaneous presence of notochord and esophageal malformations suggests a direct link between both defects, but our observation of isolated occurrence of both shows that they reflect two expressions of the profound disturbance of embryonic para-axial organization responsible for the cluster of malformations rather than a cause-effect association.
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  • 25
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    Amino acids 17 (1999), S. 301-313 
    ISSN: 1438-2199
    Keywords: Amino acids ; Taurine ; Transporter ; Rat ; Brain ; Heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In pro- and eucaryotic life, cellular and subcellular compartments are separated by membranes and the regulated and selective passage of specific molecules across these membranes is a basic and highly conserved principle. We were interested whether taurine, a naturally occuring amino acid, would be able to induce or suppress expression of transporters with the Rationale that taurine was shown to detoxify a series of endogenous toxins and xenobiotics of various chemically non-related structures. For this purpose we used a gene hunting technique, subtractive hybridization, subtracting mRNAs of taurine-treated rat brain and heart from untreated controls. Subtracted mRNAs were then converted to cDNAs, amplified, sequenced and identified by gene bank data. We found five transporter transcripts, the phosphonate transport ATPase PHNC, multidrug transporter homolog MTH104, protein-exportmembrane protein SECD, oligopeptide transporters oppA and oppD, in the brain and two: ABC-transporter BRAF-2 and cation-transport ATPase PACS, in the heart. Homologies of the sequences found were in any case 〉50% thus permitting the identification of transporters with high probability. The biological meaning could be that a naturally occuring amino acid, taurine, modulates complex transport systems. The most prominent finding is the upregulation of a multidrug transporter transcript, explaining a mechanism for the nonselective detoxifying action of taurine.
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  • 26
    ISSN: 1438-2199
    Keywords: Amino acids ; Taurine ; Osmoregulation ; Rat ; Osmolarity sensor protein ENVZ
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Although the involvement of taurine in osmoregulation is well-documented and widely accepted, no detailed mechanism for this function has been reported so far. We used subtractive hybridization to study mRNA steady state levels of genes up- or downregulated by taurine. Rats were fed taurine 100mg/kg body weight per day for a period of three days and hearts (total ventricular tissue) of experimental animals and controls were pooled and used for mRNA extraction. mRNAs from two groups were used for subtractive hybridization. Clones of the subtractive library were sequenced and the obtained sequences were identified by gen bank assignment. Two clones were found to contain sequences which could be assigned to the osmolarity sensor protein envZ, showing homologies of 61 and 65%. EnvZ is an inner membrane protein in bacteria, important for osmosensing and required for porine gene regulation. It undergoes autophosphorylation and subsequently phosphorylates OmpR, which in turn binds to the porin (outer membrane protein) promoters to regulate the expression of OmpF and OmpC, major outer membrane porines. This is the first report of an osmosensing mechanism in the mammalian system, which was described in bacteria only. Furthermore, we are assigning a tentative role for taurine in the osmoregulatory process by modifying the expression of the osmoregulatory sensor protein ENVZ.
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  • 27
    ISSN: 1437-7799
    Keywords: Key words Desferrioxamine ; Cadmium ; Metallothionein ; Nephrotoxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Desferrioxamine (DFO) a chelating agent, is used to treat metal toxicity caused by iron and aluminum in patients on hemodialysis. We hypothesized that DFO could also be used to treat cadrium-induced nephropathy. Animal experiments were therefore performed to explore whether DFO removed cadmium (Cd) from the kidneys of rats with a Cd burden. Methods. Rats received subcutaneous injections of Cd chloride (3 mg Cd/kg per day, days 0–7) followed by DFO (50 mg/kg per day, days 8–14). Levels of Cd were determined in liver, kidneys, and plasma. Enzymes assays and histopathological examination were performed in kidneys. Results. In liver, Cd injections elevated Cd levels; subsequent injections of DFO lowered the Cd levels compared with levels after injections of Cd alone. In kidneys, Cd injections increased levels of total Cd and Cd bound to cellular membranes (Mem-Cd), and decreased leucine aminopeptidase (LAP) activity (a marker of renal injury); subsequent injections of DFO elevated levels of total Cd and Mem-Cd, and lowered LAP activity compared with fundings after the injection of Cd alone. After the injections of Cd alone and DFO following Cd the renal levels of Cd were below the critical concentration required to cause renal injury, since no histopathological changes were observed in the kidney. Conclusion. DFO administration to Cd-burdened rats removed Cd from the liver, but led to accumulation of Cd in the kidneys, particularly in the cellular membranes. These results suggest that if DFO is given long-term to Cd-burdened patients, the Cd level in kidneys, particularly in renal cellular membranes, could reach concentrations that could cause manifest renal injury.
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  • 28
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Rat ; Glucocorticoid ; Antenatal therapy ; Insulin-like growth factor I and II ; Reverse transcription-polymerase chain reaction (RT-PCR)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is increasing evidence to suggest that insulin-like growth factors (IGF) I and II play a crucial role in fetal lung development. Expression of IGF-I and II has been demonstrated to be predominant during fetal life and decreases prior to birth. Antenatal glucocorticoids are reported to improve lung immaturity. The aim of this study was to investigate the effect of antenatal glucocorticoid administration on IGF-I and II expression in nitrofen-induced congenital diaphragmatic hernia (CDH) in rats. A CDH model was induced in pregnant rats following administration of 100 mg nitrofen on day 9.5 of gestation (term = 22 days). Dexamethasone (0.25 mg/kg) was given intraperitoneally on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21. The fetuses were divided into three groups: I, normal controls; II, nitrofen-induced CDH; and III, nitrogen-induced CDH with antenatal dexamethasone treatment. mRNA was extracted from whole lung and a reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the relative amounts of IGF I and II mRNA. Levels of mRNA were expressed as a ratio of the band density divided by that of β-actin, a housekeeping gene known to be expressed at a constant level. Immunohistochemistry using anti-rat IGF I and II antibody was also performed in each group. Levels of IGF I mRNA were significantly increased in group II (0.50 ± 0.08) compared to group I (0.34 ± 0.10) or group III (0.32 ± 0.06) (P 〈 0.05). Levels of IGF II mRNA were also significantly increased in group II (0.95 ± 0.20) compared to group I (0.42 ± 0.07) or group III (0.31 ± 0.09) (P 〈 0.05). Strong IGF I and II expression was observed in the hypoplastic CDH lung (group II), mainly in the bronchiolar epithelium. IGF I and II expression in group I and III lungs was either absent or weak. The finding of significant reductions in IGF I and II mRNA and protein levels in dexamethasone-treated CDH lung suggest that dexamethasone may accelerate the fetal stage of lung development.
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  • 29
    ISSN: 1437-9813
    Keywords: Key words Unilateral undescended testis ; Rat ; Testicular injury ; DNA flowcytometry ; Anti-sperm antibody
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study was designed to evaluate whether creation of a unilateral undescended testis (U/L UDT) in rats by direct fixation of the testis can lead to changes in the contralateral (C/L) descended testis, and if so, whether this inherent problem of the model could be eliminated by anchoring the divided gubernaculum to indirectly fix the testis. Thirty male newborn rats were divided into three groups of 10 each and the procedure done on the 2nd day of life to create U/L UDT according to the group allocated: group I: sham-operated; group II: anchoring the gubernaculum after gubernaculectomy; group III: Direct suture fixation of the testis. Fertility, C/L testicular weight (TW), Johnsen score, seminiferous tubular diameter (STD), DNA flowcytometry, and serum anti-sperm antibodies (ASA) were studied. Fertility, C/L TW, Johnsen score, STD, and haploid cell population were significantly reduced in group III compared to group II, while significantly higher titers of ASA were found in group III. Gubernaculectomy and anchoring the gubernaculum to the anterior abdominal wall is a better technique of creation of experimental UDT, as direct fixation of the testis is potentially detrimental to the C/L normal, descended testis.
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  • 30
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    Pediatric surgery international 15 (1999), S. 457-460 
    ISSN: 1437-9813
    Keywords: Key words Blunt testicular injury ; Rat ; DNA flowcytometry ; Antisperm antibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Injury to the testis breaching the tunica albuginea is known to affect fertility. Blunt testicular trauma with an intact tunica albuginea has been reported to have no effect on contralateral testicular histology and Johnsen testicular maturation score. However, sensitive techniques like DNA flowcytometry have not been utilized so far to evaluate contralateral testicular germ-cell changes. Sixty-four male Wistar rats aged 20 days were randomized into groups I (control), II (unilateral blunt testicular trauma, UBTT), III (UBTT and excision of ipsilateral testis at 6 h), and IV (UBTT and cyclosporine for 30 days). Fertility, DNA flowcytometry of contralateral testicular tissue, and anti-sperm antibodies (ASA) were evaluated. Fertility and haploid-cell percentage of the contralateral testis were significantly decreased compared to controls in early adulthood (100 days). Around 150 days of age, as ASA decreased significantly, fertility and contralateral testicular haploid-cell population recovered and were comparable to the controls. Excision of the traumatized testicle around 6 h after injury or administration of cyclosporine for 30 days protected fertility and the contralateral testis. In contrast to group II rats, ELISA for ASA was negative in group III and IV rats. UBTT affects the contralateral testis and fertility. ASA mediate this damage. Orchidectomy performed around 6 h after trauma or short-term cyclosporine therapy prevents the damage.
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  • 31
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    Amino acids 17 (1999), S. 139-148 
    ISSN: 1438-2199
    Keywords: Amino acids ; Polyamine oxidase ; Polyamines ; Gender ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Variations in level of polyamines and their related enzymes are frequently observed in response to some treatments which affect in a different way male and female. The possibility of a gender-related difference in the oxidation of polyamines was investigated in rats by measuring the activity of polyamine oxidase, a ubiquitous enzyme of vertebrate tissues, which transforms spermine into spermidine and spermidine into putrescine. The study was carried out on thymus, spleen, kidney and liver of young rats of both sexes, and female rats showed a lower polyamine oxidase activity than male rats in all the tissues. We also found higher values of spermidine acetylation in female than male rats in thymus and liver. Owing to these gender-related differences, a higher spermidine N-acetyltransferase/ polyamine oxidase ratio was found in female than in male rats. A second gender-related difference was a higher spermidine/spermine ratio in female than in male, the only exception being the thymus. These basal differences possibly account for the gender-related differences of polyamine metabolic enzyme activities in response to some treatments, including drugs or hormones.
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  • 32
    ISSN: 1432-2307
    Keywords: Key words Pyruvate kinase isoenzymes ; N-Nitrosomorpholine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The expression of the pyruvate kinase (PK) isoenzymes L and M2 was analysed in the livers of rats treated with the hepatocarcinogenic agent N-nitrosomorpholine (NNM) in the drinking water. In control animals L-PK expression was restricted to liver parenchymal cells, whereas M2-PK was detected in bile duct epithelial, blood vessel wall, endothelial and Kupffer cells. In rats treated with NNM proliferating oval cells were consistently L-PK negative and M2-PK positive, while the ductal cells of cholangiofibroses were clearly L-PK positive and coexpressed M2-PK. However, no morphological differentiation of ductal cells into hepatocyte-like cells was observed. In the clear and acidophilic cell foci storing glycogen in excess strong staining for L-PK was observed. In glycogen-poor foci induced by NNM a shift from L-PK to M2-PK expression takes place.
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  • 33
    ISSN: 1432-2307
    Keywords: Key words Medullary thyroid carcinoma ; Basement membrane ; Laminin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Medullary thyroid carcinoma (MTC) originates from C cells, which secrete calcitonin (CT), their specific marker. C cells are located in contact with the basement membrane (BM) of the thyroid follicles, which is partly made up of the laminin-2 isoform synthesized by thyrocytes. During oncogenesis, proliferation of the C cells, invading the centre of the follicles, leads to a break in their normal contact with the BM. As specific interactions of cells with BM components, especially laminins, are important for proliferation and differentiation, we investigated the relationships of normal and neoplastic C cells with laminin in the Wag/Rij rat model of human MTC. Immunocytochemical studies showed a progressive loss of the laminin layer underlying the hyperplastic C cell nodules around the large dedifferentiated tumours. The α2, β1 and γ1 chains of the laminin-2 isoform were synthesized and secreted by rat MTC 6–23 cell cultures and the tumours induced by subcutaneous injection of these cells. In situ hybridization combined with anti-CT immunocytochemistry showed a low expression of α2 mRNA on differentiated C cells and thyrocytes, but an overexpression on immunonegative spontaneous MTC and induced intrathyroid tumours. The high level of α2 gene expression, together with tumour dedifferentiation, suggests a relationship with malignancy.
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  • 34
    ISSN: 1433-0350
    Keywords: Key words Hydrocephalus model ; Kaolin ; Micro-balloon ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We used three types of specialized micro-balloons 0.7–1.35 mm in outer diameter instead of kaolin to develop a reproducible rat model of hydrocephalus with a low experimental mortality. The micro-balloon was inserted 6 mm deep into the cisterna magna via a burr hole immediately behind the lambda. The angle of introduction was 50°. We also set up kaolin-induced hydrocephalic models in 25 rats as controls. The kaolin model revealed 52% mortality with an 80% induction rate of hydrocephalus, while the balloon model showed 9% mortality with a 60% induction rate. Balloon-induced hydrocephalus was maximal at 1 week and tended to decrease after 2–3 weeks. The pathological findings were not different between the two models. We concluded that the micro-balloon model for hydrocephalus is an easily reproducible model with low experimental mortality.
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  • 35
    ISSN: 1432-0851
    Keywords: Key words Transgenic ; Rat ; EGP-2 ; GA733-2 ; Immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), also known as 17-1A or Ep-CAM, is a 38-kDa transmembrane antigen, commonly used for targeted immunotherapy of carcinomas. Although strongly expressed by most carcinomas, EGP-2 is also expressed in most simple epithelia. To evaluate treatment-associated effects and side-effects on tumor and normal tissue respectively, we generated an EGP-2-expressing transgenic Wistar rat. To express the cDNA of the EGP-2 in an epithelium-specific manner, the 5′ and 3′ distal flanking regions of the human keratin 18 (K18) gene were used. EGP-2 protein expression was observed in the liver and pancreas, whereas EGP-2 mRNA could also be detected in lung, intestine, stomach and kidney tissues. In this rat, EGP-2-positive tumors can be induced by injecting a rat-derived carcinoma cell line transfected with the GA733-2 cDNA encoding EGP-2. Transgenic rats were used to study specific in vivo localization of an i.v. anti-EGP-2 monoclonal antibody, MOC31, applied i.v. Immunohistochemical analyses showed the specific localization of MOC31 in s.c. induced EGP-2-positive tumors, as well as in the liver. In contrast, in EGP-2-transgenic rats, MOC31 did not bind to EGP-2-negative tumors, the pancreas, or other normal tissues in vivo. In conclusion, an EGP-2-transgenic rat model has been generated that serves as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities.
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  • 36
    ISSN: 1432-2013
    Keywords: Key words AMPA receptor-mediated EPSCs ; Cyclothiazide ; Hippocampus ; Kinetics ; Long-term potentiation (LTP) ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We have analysed whether the expression of long-term potentiation (LTP) in rat hippocampal CA1 neurons involves a change in the kinetics of (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) (AMPA-EPSCs) or their susceptibility to the AMPA receptor modulator cyclothiazide. AMPA-EPSCs in the CA1 region were evoked by alternate stimulation of two independent Schaffer collateral-commissural inputs of slices of adult rat hippocampus. In the current-clamp mode a strong tetanus (100 Hz, 1 s) applied to one input (input I) induced stable LTP of AMPA-EPSCs in this input, while the control input (input II) remained unaffected. For neither input were EPSC rise time and decay kinetics significantly changed. The application of cyclothiazide prolonged the rise time and the decay time constants of the AMPA-EPSCs in both control and potentiated inputs to the same extent (Input I–rise time: 198±8%, decay: 148±12%; input II–rise time: 212±14%, decay: 144±19%; n=8). Furthermore, when present during tetanization cyclothiazide did not occlude LTP, suggesting that cyclothiazide and tetanic stimulation enhance AMPA-EPSCs via independent mechanisms. Our findings argue against changes in (de-)activation or desensitization of AMPA receptors as the molecular basis for the expression of LTP.
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  • 37
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    Pflügers Archiv 437 (1999), S. 910-916 
    ISSN: 1432-2013
    Keywords: Key words Cardiorespiratory system ; Anaesthesia ; Rat ; Rabbit ; Guinea-pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Cardioventilatory coupling is a temporal coherence of respiratory and cardiac rhythms, seen in humans at rest, and during sleep and anaesthesia. In this study we compared the cardioventilatory coupling of anaesthetised rabbits, rats and guinea-pigs. Breathing two successive anaesthetic concentrations (1 or 2% isoflurane) we compared the effect of anaesthetic depth and species on (1) heart rate, (2) heart rate variability, (3) ventilatory rate (f), (4) ventilatory variability, (5) ratio HR/f, (6) degree of coupling (Shannon entropy of the distribution of intervals between inspiration and the preceding electrocardiographic R wave – the RI interval) and (7) coupling pattern, classified into four sub-patterns (I-IV) based upon inspection of the RI interval time series. Rabbits exhibited significantly less ventilatory variability and coupling than rats or guinea-pigs. The sub-pattern of coupling also differed between the three species. Rabbits showed coupling only when HR and f were close to integer ratios whereas other species coupled at non-integer ratios. Ventilatory variability in the rat and guinea-pig differed according to the pattern of coupling observed. Of the three species studied, the rat and guinea-pig demonstrated coupling most similar to that of anaesthetised human subjects. Anaesthetic concentration did not influence the pattern or degree of coupling.
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  • 38
    ISSN: 1432-1912
    Keywords: Key words Blood pressure ; Endothelium ; Human ; Mesenteric artery ; Rat ; Smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75–1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. How-ever, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the β-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2+-induced contractions in human arteries.
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  • 39
    ISSN: 1432-1912
    Keywords: Key words Asphyxia ; Nitric oxide ; Electron spin ; resonance ; Adrenocorticotropin ; Resuscitation ; S-Methylisothiourea ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Anaesthetized rats, endotracheally intubated and mechanically ventilated with room air, were subjected to a 5-min period of asphyxia by turning off the ventilator. The ventilator was then turned back on and, simultaneously, the animals were treated with either the adrenocorticotropin fragment 1–24 [ACTH-(1–24), 160 µg/kg in a volume of 1 ml/kg i.v.] or an equivalent volume of saline. Nitric oxide (NO)-haemoglobin formation was detected ex vivo in arterial blood by electron spin resonance spectrometry; arterial blood pressure, electrocardiogram (ECG) and electroencephalogram (EEG) were monitored for a 60-min observation period, or until prior death. During asphyxia, there was massive formation of NO (red cell concentrations 40–80 µM), associated with a dramatic fall in mean arterial pressure and pulse pressure, marked bradycardia and ECG signs of ischaemic damage, as well as an isoelectric EEG. Treatment with ACTH-(1–24) produced a prompt (within 15 min) and long-lasting drop in NO blood levels, associated with an almost immediate (within 1 min) restoration of cardiovascular function and with a more gradual recovery of EEG, which became normal after 30–40 min; all parameters remained stable throughout the 60-min observation period. In saline-treated rats, on the other hand, there was a further increase in NO blood levels, as detected 3 min after treatment, and all died within 5–8 min. Moreover, pretreatment and treatment with S-methylisothiourea sulphate (SMT, 3 mg/kg i.v.), a relatively specific inhibitor of inducible NO synthase, inhibited NO formation, but did not affect the mortality rate (100% within 5–8 min). The present results provide the first evidence that prolonged asphyxia is associated with high blood concentrations of NO, and that the life-saving effect of melanocortin peptides in severe hypoxic conditions is associated with a complete normalization of NO blood levels. However, the lack of SMT protection in this experimental model seems to rule out the possibility that the ACTH-(1–24)-induced resuscitation is due to an effect on NO overproduction.
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  • 40
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    Naunyn-Schmiedeberg's archives of pharmacology 359 (1999), S. 117-122 
    ISSN: 1432-1912
    Keywords: Key words Ethanol ; Restraint stress ; NMDA receptor complex ; Memantine ; Drug discrimination ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is a large body of experimental evidence that both stress and N-methyl-d-aspartate (NMDA) receptor antagonists may alter acute behavioural effects of ethanol. Notably, an uncompetitive, low-affinity NMDA receptor antagonist, memantine, has been recently claimed to possess anti-craving properties in rats with a long-term history of ethanol consumption. The aim of the present study was to assess the effects of restraint stress and memantine on the dose-response curve of ethanol discrimination. Rats were trained to discriminate 1 g/kg ethanol from saline in the two-lever drug discrimination procedure. When ethanol discrimination was acquired, the subjects were exposed to 30-min sessions of acute restraint stress, and different doses of ethanol (0.25, 0.5 or 1 g/kg) or saline were administered. In subsequent experiments the effects of memantine (2.25 or 4.5 mg/kg) on the cueing effects of ethanol were tested. Neither the stress sessions nor memantine influenced the ethanol discrimination dose-response curve. Moreover, the stress did not alter the rate of responding. However, both doses of memantine tended to increase the rate of responding when given in combination with lower doses of ethanol (0.25–0.5 g/kg). In contrast, 4.5 mg/kg memantine decreased the response rate when combined with 1 g/kg ethanol. These results suggest that: (1) pre-exposure to acute restraint stress or memantine does not affect the dose-response curve of ethanol discrimination; (2) memantine given in combination with low doses of ethanol may stimulate operant behaviour in the food-reinforced drug discrimination procedure.
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  • 41
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    Pediatric nephrology 13 (1999), S. 800-805 
    ISSN: 1432-198X
    Keywords: Key words In situ hybridization ; Kidney development ; Nephrogenesis ; Phosphatase activity ; Serine/threonine protein phosphatase 2A ; Protein phosphorylation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Several lines of evidence suggest that the serine/threonine protein phosphatase (PP)2A is of vital importance for cell cycle regulation, cell differentiation, and signal transduction. This prompted us to study the expression of the mRNA for PP2A catalytic isoforms α and β in the developing rat kidney using in situ hybridization histochemistry. The expression patterns of the two isoforms were strikingly similar. Both were ubiquitously expressed in early metanephric kidneys. Later in gestation they were expressed in the nephrogenic zone. Strong expression was observed on postnatal day (PN) 10. This was followed by a downregulation at PN20, i.e., when nephrogenesis is completed. The expression in the adult kidney was very weak and mainly confined to the medulla. In a phosphatase activity assay, PP2A accounted for 78% of the total serine/threonine phosphatase activity in embryonic day 15 rat kidneys. PP1 was the main contributor to the remaining activity. In conclusion, PP2A is the major serine/threonine phosphatase in fetal kidneys. The age-dependent expression pattern supports the concept that this enzyme is of particular importance during renal morphogenesis and development.
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  • 42
    ISSN: 1432-198X
    Keywords: Key words Hypercalciuria ; Idiopathic hypercalciuria ; Bone mineral content ; 1 ; 25-Dihydroxyvitamin D ; Furosemide ; Ammonium chloride ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The relationship between bone mineral status and hypercalciuria is controversial. The effect on bone composition of different forms of hypercalciuria was studied in female rats made hypercalciuric by 7-week administration of oral furosemide (F, n=12), intraperitoneal 1,25-dihydroxy vitamin D (VD, n=11), or oral ammonium chloride (AC, n=12). Seven untreated rats served as controls (C). Hypercalciuria (mg/100 g per 24 h, mean ±SEM) of F (4.3±0.2), VD (4.1±0.4), and AC (3.9±0.3) groups was of similar intensity (C rats 1.3±0.1, P〈0.01). Weight and length gains and serum CO2, sodium, potassium, calcium, and phosphate were no different among the four groups. Bone was studied by dual-energy X-ray absorptiometry of left tibiae. AC rats had significantly less bone area (1.505±0.018 cm2) than VD and C (1.602±0.020 and 1.587±0.019 cm2). Bone mineral content was decreased in F (0.357±0.007 g) and AC (0.362±0.006 g) compared with VD (0.407±0.008 g) and C (0.389±0.009 g) groups. Bone mineral density was different between F (0.231±0.002 g/cm2) and VD and C rats (0.254±0.004 and 0.245±0.003 g/cm2), and also between AC (0.240±0.003 cm2) and VD rats. In these rat models, hypercalciuria of renal origin (F) and hypercalciuria caused by acid load (AC) adversely impaired bone mass.
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  • 43
    ISSN: 1432-198X
    Keywords: Key words Cystinosis ; Cysteamine ; Renal function ; Rat ; Prenatal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The safety of cysteamine after renal transplantation and during pregnancy is an important issue, since girls with cystinosis are in better health on cysteamine therapy and thus more likely to become pregnant. In the first study, cysteamine was given to pregnant rats on days 6.5–18.5 post conception in oral doses of 0, 37.5, 75, 100, and 150 mg/kg per day. The dams were sacrificed on day 20.5, the fetal kidneys removed and prepared for histological examination. In the second study, cysteamine was given to dams on days 6.5–19.5 post conception in oral doses of 0, 37.5, 50, and 75 mg/kg per day. Dams were allowed to give birth naturally and pups were given cysteamine on days 4–21 to yield the same oral doses of cysteamine given to the dam. Renal function was evaluated on day 35. Histological examination of fetal kidneys revealed no changes even in kidneys from fetuses with growth retardation and malformations. Furthermore, there were no alterations in renal function in offspring on day 35. These findings demonstrate that cysteamine therapy does not affect renal development in the rat. Further investigations will be required to prove whether cysteamine therapy has the potential to affect renal development in the human.
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  • 44
    ISSN: 1432-2072
    Keywords: Key words Ethanol ; Limited access ; Nicotine ; Mecamylamine HCl ; Rat ; Voluntary intake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Observations in humans suggest that the initial use of tobacco occurs in close temporal proximity to experimentation with alcohol. There have been relatively few research reports, however, examining possible interactions between these two agents. The present experiments examined the effect of nicotine exposure on the acquisition of ethanol drinking behavior in a limited access procedure. In experiment 1, rats were presented with 1-h access to ethanol solutions of increasing concentration for a period of 20 days. Subcutaneous injections of nicotine (0.6 or 1.2 mg/kg salt) or vehicle were administered 30 min prior to each ethanol presentation. Experiment 2 used a similar method, but rats were presented with water along with ethanol during the 1-h test session. Mecamylamine, a nicotinic receptor antagonist, was administered 30 min prior to the nicotine treatment. Nicotine was seen to produce a dose-dependent increase in ethanol drinking behavior which commenced at the 5% ethanol concentration and continued at 8% and again at 10%. In the second experiment, mecamylamine was observed to block completely the nicotine-induced increase in ethanol drinking behavior. The findings suggest that exposure to nicotine can facilitate the acquisition of ethanol drinking behavior in naive rats and that this effect is mediated by nicotine’s interaction at the nicotinic-cholinergic receptor.
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  • 45
    ISSN: 1432-2072
    Keywords: Key words Chlordiazepoxide ; FG 7142 ; Rat ; Diencephalic amnesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The intralaminar thalamic nuclei (ILn) have been implicated as a critical site of pathology in amnesia. Lesions of the ILn have been found to produce behavioral effects comparable to benzodiazepine (BDZ) receptor agonists. We compared the effects of chlordiazepoxide (CDP), a BDZ agonist, and FG 7142, a partial inverse agonist at the BDZ receptor, in rats with thalamic lesions and in unlesioned controls. Delayed matching-to sample (DMS) performances were studied during treatment with ascending doses of CDP, counterbalanced trials with 2.5 mg/kg CDP and saline, ascending doses of FG 7142, and (for unlesioned controls only) counterbalanced trials with saline and higher doses of CDP. CDP had effects similar to the ILn lesion, decreasing response speed and percent correct responding in a delay-independent fashion. These effects were additive with the impairments associated with the ILn lesion. The effects of FG 7142 were more complex. At lower doses, it increased response speed without affecting response accuracy. At higher doses, it diminished both the speed and the accuracy of DMS responding. These results support the hypothesis that ILn lesions and BDZ agonists have similar effects on DMS performance. The biphasic effects observed for FG 7142 are consistent with other evidence that low doses of this drug enhance while higher doses impair memory performance. Although DMS accuracy was not improved, the enhancement observed for response speed provides evidence that partial inverse BDZ agonists have potential utility as treatments for cognitive impairments associated with amnesia.
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  • 46
    ISSN: 1432-2072
    Keywords: Key words Male sexual behavior ; Sexual impotence ; Plant extracts ; Turnera diffusa ; Pfaffia paniculata ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sexually potent and sexually sluggish/impotent male rats were treated orally with different amounts of Turnera diffusa and Pfaffia paniculata fluid extracts (0.25, 0.50, 1.0 ml/kg). While having no effect on the copulatory behavior of sexually potent rats, both plant extracts – singly or in combination – improved the copulatory performance of sexually sluggish/impotent rats. The highest dose of either extract (1 ml/kg) (as well as the combination of 0.5 ml/kg of each extract) increased the percentage of rats achieving ejaculation and significantly reduced mount, intromission and ejaculation latencies, post-ejaculatory interval and intercopulatory interval. Neither extract affected locomotor activity. These results seem to support the folk reputation of Turnera diffusa and Pfaffia paniculata as sexual stimulants.
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  • 47
    ISSN: 1432-2072
    Keywords: Key words BC264 ; Cholecystokinin ; CCKB receptor ; Memory ; Ageing ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: The implication of CCKB receptors in cognitive processes is far from fully understood. Objective: The present study investigated the effect of propionyl-BC264, a selective agonist of CCKB receptors, in young and old rats. Methods: Cognitive functions were studied in a two-trial recognition memory task developed in our laboratory. Results: It was shown that propionyl-BC264 enhanced information processing in young as well as in old rats when injected (10 μg/kg; IP) immediately after the acquisition phase and before the retrieval trial but not before the acquisition trial. This cognitive enhancing effect was blocked by prior administration of L 365,260, a selective CCKB receptor antagonist. Conclusions: In view of the fact that BC264 is devoid of anxiogenic effects, it could be of value in the treatment of cognitive impairments associated with both normal and pathological ageing.
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  • 48
    ISSN: 1432-2072
    Keywords: Key words Baclofen ; Cocaine ; Extinction ; Intravenous self-administration ; Maintenance dose ; Rat ; Reinstatement of responding ; Relapse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Recent studies suggest that the GABAB receptor agonist, baclofen, may be a useful pharmacotherapy for cocaine abuse. Objectives: To investigate further the effects of baclofen on maintenance and reinstatement of cocaine-reinforced behavior in rats. Methods: Two groups of rats were trained to self-administer IV cocaine (0.2 or 0.4 mg/kg per infusion) during daily 7-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with baclofen (1.25, 2.5 or 5 mg/kg IP) or saline before the session for 5 consecutive days. An additional group of rats was trained to self-administer IV cocaine (0.4 mg/kg per infusion) during the first 2 h of daily 7-h sessions. Cocaine was replaced by saline for the remaining 5 h of the session. Once behavior had stabilized over the 7-h period, priming injections of saline (IV), cocaine (3.2 mg/kg IV) or baclofen (1.25 or 2.5 mg/kg IP) were administered prior to hour 4. Injections of baclofen (1.25 or 2.5 mg/kg IP) or saline were also given before priming injections of cocaine. Results: Pretreatment with the two higher doses of baclofen (2.5 and 5 mg/kg) decreased the number of cocaine infusions in both maintenance groups (0.2 and 0.4 mg/kg) over the 5-day treatment period. Baclofen had a greater suppressant effect on responding maintained by the lower dose of cocaine. Priming injections of baclofen (1.25 and 2.5 mg/kg) or saline did not reinstate responding. However, these same doses of baclofen dose-dependently reduced the reinstatement of responding produced by priming injections of cocaine. Conclusions: 1) The magnitude of the suppressant effects of baclofen on maintenance of cocaine self-administration depends upon the maintenance dose, 2) baclofen may be useful in preventing reinstatement of cocaine-seeking behavior, and 3) compared to maintenance, reinstatement of responding is more sensitive to the suppressant effects of baclofen.
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  • 49
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    Psychopharmacology 143 (1999), S. 318-321 
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Cotinine ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence.
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  • 50
    ISSN: 1432-2072
    Keywords: Key words NMDA (N-methyl-D-aspartate) ; Schizophrenia ; Prepulse inhibition (PPI) ; Sensory gating ; P50 ; Auditory evoked potentials (AEP) ; Ketamine ; d-Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, IP) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, IP) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.
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  • 51
    ISSN: 1432-2072
    Keywords: Key words Dezocine ; Morphine ; 7-OH-DPAT ; Quinpirole ; SKF38393 ; SCH23390 ; Rat ; Warm-water tail-withdrawal ; Antinociception
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: The purpose of the present investigation was to evaluate the effects of the D3 agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D3 agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D3/D2 agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D2/D3 antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D1 agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D1 antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D3, and possibly the D2, receptor can modulate μ agonist-induced antinociception.
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  • 52
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    Psychopharmacology 144 (1999), S. 311-315 
    ISSN: 1432-2072
    Keywords: Key words Anxiety ; ACTH ; Corticosterone ; GH ; Stress ; Anxiolytic ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to ”isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isolation deprives animals of mild daily stressors that are inherent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, repeated stressors may abolish the effects of isolation. Objectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abolish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the elevated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxiolytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk assessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of ”isolation stress”. However, isolation was anxiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation.
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  • 53
    ISSN: 1432-2072
    Keywords: Key words GABAA receptor ; Propofol ; Midazolam ; NMDA receptor ; Ketamine ; Noradrenaline ; Medial prefrontal cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: N-Methyl-d-aspartate (NMDA) receptor antagonism and GABAA receptor activation are believed to be critical targets for general anesthetic action. However, as NMDA antagonism of intravenous anesthetic agents causes post-anesthetic emergence reactions such as hallucination and agitation, while the GABAA-mimetic intravenous anesthetic agents do not, these two classes of intravenous anesthetic agents produce differential clinical profiles. Objective: We have investigated the differential effects of the GABAA agonists propofol and midazolam and the NMDA antagonist ketamine on noradrenaline release from the medial prefrontal cortex of the rat using microdialysis, as noradrenergic neurons have a role to play in anesthesia and are known to be important in the control of sleep, attention and learning. Methods: Twenty-one male Wistar rats (200– 270 g) were randomly allocated into three groups: ketamine 100 mg.kg–1 (n=6), propofol 60 mg.kg–1 (n=8) and midazolam 5 mg.kg–1 (n=7) IP. A unilateral guide cannula was implanted stereotaxically into the medial prefrontal cortex under pentobarbital anesthesia (50 mg.kg–1 IP). Forty-eight hours later, a dialysis probe was inserted through the guide cannula, and perfused with an artificial cerebrospinal fluid solution containing 1 mM pargyline. Following an equilibration period, samples of dialysate were collected every 10 min. Noradrenaline content was measured by high-performance liquid chromatography using an electrochemical detector. Results: Anesthesia times, defined as the duration between the loss of righting reflex and recovery, were 24.7±5.6 (SEM), 20.5±1.9 and 25.2±1.5 min for propofol, midazolam and ketamine, respectively (no significant between-group differences). Both GABAA agonists, propofol and midazolam, significantly decreased noradrenaline release (75% and 71% of basal release, respectively). The NMDA antagonist ketamine markedly increased noradrenaline release (413% of basal). Conclusion: These data suggest that different clinical profiles observed with these two classes of sedatives may result from changes in noradrenaline release from the medial prefrontal cortex.
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  • 54
    ISSN: 1432-2072
    Keywords: Key words Compulsion ; Addiction ; Cocaine ; Amphetamine ; Cannabis ; Phencyclidine ; Nucleus accumbens ; Amygdala ; Frontal cortex ; Limbic ; Stimulus-reward association ; Conditioned reward ; Sensitization ; Drug-seeking ; Inhibitory control ; Cognition ; Conditioned stimulus ; Incentive motivational ; Dopamine ; Rat ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.
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  • 55
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    Psychopharmacology 146 (1999), S. 400-412 
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Delay of reward ; Impulse control ; Muscimol ; pCPA ; Rat ; Serotonin ; Serotonin reuptake inhibitors ; 5-HT1A receptor ligands ; 5,7-DHT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes. Objective: The present study further examined the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer. Methods: Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65–70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s. Results: In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABAA receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1–2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4–8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT1A receptor agonist, 8-OH-DPAT (0.015–0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1–4 mg/kg IP), ipsapirone (0.5–1 mg/kg IP) and MDL 73005EF (1–2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg). Conclusions: These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT1A receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.
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  • 56
    ISSN: 1432-2072
    Keywords: Key words Ethanol ; Serotonin ; Delayed reinforcement ; Self-control ; Impulsivity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Tolerance to delay of reinforcement has been proposed as an important facet of self-control in both animals and man. Poor self-control, leading to impulsive behaviour, can be a major problem if it reaches pathological levels. Objectives: The effects of five serotonergic drugs were compared to those of ethanol on a procedure for measuring tolerance to delay of reinforcement in rats in order to elucidate further the role of the serotonin systems in the regulation of impulsive behaviour. Methods: Rats were trained to choose between a single food pellet (small reinforcer) delivered immediately or five food pellets (large reinforcer) delivered after programmed delays. At the start of each session, there was no delay between the response and delivery of the large reinforcer, but this was increased stepwise during the session to delays of 10, 20, 40 and 60 s. Results: The rats showed consistent preference for the larger reinforcer when it was not delayed but showed a shift in preference as the session continued, so that they preferred the small reinforcer when the large was delayed by 40 or 60 s. Ethanol at a dose of 1.0 g/kg produced a significance increase in preference for the small, immediate reinforcer throughout the session, although there were marked individual differences in the size of the effect. A similar, but somewhat smaller effect was seen with the 5-HT2 agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT1A agonist, 8-OH-DPAT (0.3 mg/kg) reduced preference for the large reinforcer at the start of the session, and reduced preference for the small reinforcer at the end of the session, i.e. produced a regression to indifference. Lower doses of these three drugs, and treatment with the 5-HT receptor subtype selective antagonists WAY-100635 (5-HT1A: 0.01–0.1 mg/kg), ritanserin (5-HT2: 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT3: 1.0 and 3.0 mg/kg) had no significant effects on reinforcer choice. Conclusion: These data show that ethanol and DOI increase preference for the immediate reinforcer, which can be construed as evidence of an increase in impulsive behaviour (reduction in self control), whereas selective blockade of the 5-HT1A, 5-HT2 or 5-HT3 receptors using selective antagonists does not affect self-control.
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  • 57
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    Psychopharmacology 146 (1999), S. 432-439 
    ISSN: 1432-2072
    Keywords: Key words Impulsivity ; Choice ; Delay ; Methamphetamine ; Drug abuse ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Moderate doses of d-amphetamine (given both acutely and chronically) have been shown to decrease impulsivity in children with attention deficit hyperactivity disorder (ADHD) and to improve attention and learning in normal adults. In contrast, chronic doses of methamphetamine (METH) in drug abusers have been associated with increased impulsivity, and impairments in learning and attention. Objectives: We report the effects of METH on an animal model of impulsive behavior. Methods: Rats were tested using the adjusting amount (AdjAmt) procedure in which the animals choose between a delayed fixed (large) amount of water and an immediate adjusting (small) amount of water. In the acute METH study, rats were given a single dose of 0.5, 1.0, 2.0, and 4.0 mg/kg METH or saline 30 min before testing. In the chronic METH study, we determined the effects of the 4.0 mg/kg dose of METH injected chronically 1 h after behavioral testing for 14 days. Thus the rats were tested using the AdjAmt procedure 22 h after injections of METH or saline. Results: After 0.5, 1.0 and 2.0 mg/kg METH, the rats valued the delayed large rewards more than after saline, indicating that the METH decreased impulsiveness. At the 4.0 mg/kg dose, the rats failed to respond. Rats treated repeatedly with the post-session large behaviorally disruptive dose of METH valued the delayed large rewards less than the saline-treated rats, indicating that this dosing regimen of METH increased impulsiveness. Conclusions: In these experiments, the rats became less impulsive after acute non-disruptive doses of pre-session METH, whereas they became more impulsive after receiving repeated post-session injections of a dose that was behaviorally disruptive when administered acutely.
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  • 58
    ISSN: 1432-2072
    Keywords: Key words Ibogaine ; Cocaine ; Dose-response ; Locomotor activity ; Sensitization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. Objectives: To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. Methods: Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). Results: Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. Conclusions: These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal.
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  • 59
    ISSN: 1432-2072
    Keywords: Key words Oxytocin ; SSRIs ; Depression ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The nonapeptide oxytocin is released into systemic circulation in situations of psychosocial interaction, and has been shown to be involved in mechanisms of social bonding and social recognition in laboratory studies. In view of disturbances in psychosocial relationships being a triggering factor for depression and anxiety, it is interesting to note that experimental studies have shown oxytocin to possess antidepressant- and anxiolytic-like actions. Thus, in the present study we examined effects of the SSRI citalopram (20 mg/kg IP) on plasma oxytocin, acutely and upon repeated administration, in adult male Sprague-Dawley rats. Plasma oxytocin, and some functionally related peptides (CCK, gastrin, somatostatin and insulin), were measured by standard radioimmunoassay techniques. Acute citalopram administration produced a statistically significant increase in plasma oxytocin and CCK levels. Administration of citalopram for 14 days did not attenuate the oxytocin-releasing effect to a challenge dose of the SSRI zimeldine (20 mg/kg SC), whereas CCK levels were not increased after the subchronic citalopram treatment. Thus, the SSRI citalopram produces increased plasma oxytocin levels acutely, and there appears to be no or little tolerance to this effect upon repeated administration. There were no, or variable, effects on plasma levels of gastrin, somatostatin or insulin. It is suggested that oxytocin release is an important aspect of the pharmacological actions of SSRIs, and this could be an important contributory factor for the clinical profile of this group of antidepressants with particular efficacy in disorders of psychosocial origin.
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  • 60
    ISSN: 1432-2072
    Keywords: Key words Alcoholism ; Alcohol drinking ; Alcohol intake ; Calcium channells ; Genetic model of alcoholism ; Pharmacotherapy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Drugs which possess selective actions on a given voltage operated calcium (Ca2+) channel (VOCC) are reportedly involved in the pharmacological actions of alcohol. Recently it was shown that the 1,4-dihydropyridine (−)-BAY k 8644, an L-type VOCC agonist, reduces alcohol intake relatively selectively in the genetic drinking AA rat. This study determined whether (−)-BAY k 8644 would alter volitional alcohol drinking in two other genetic models of alcoholism, male P rats and a new strain of male and female high ethanol preferring (HEP) rats. By use of a standard 10-day preference test for water versus 3 to 30% alcohol, the maximally preferred concentration of alcohol was first determined for each rat individually, i.e. 9%, 13% or 15%. Then the rats were allowed free access over 24 h or limited access to alcohol for only 2 h, during which time the intakes of water and preferred solution of alcohol were recorded. After the drinking patterns stabilized for 4 days, saline, a solutol vehicle solution or (−)-BAY k 8644 was administered: (1) in a dose of 0.125, 0.25 or 0.5 mg/kg given intraperitoneally twice daily for 4 days during free access to alcohol; and (2) for 3 days in a dose of 0.125 or 0.25 mg/kg given subcutaneously 30 min prior to 2 h of limited access to alcohol. Fluid intakes were recorded for either 4 or 8 days after limited and free access conditions, respectively. Whereas the control solutions were without effect during 24 h access, (−)-BAY k 8644 caused a significant dose-dependent suppression of up to 80% in absolute g/kg and proportion of alcohol to total fluid consumed; this decline persisted in the post drug period. During the limited access paradigm, (−)-BAY k 8644 similarly reduced alcohol drinking maximally within the first 15 min of presentation of alcohol; again, this reduction persisted over the remaining 105 min of alcohol access. Also, individual levels of blood alcohol declined concurrently with the suppression of drinking. These results demonstrate that (−)-BAY k 8644 possesses a short latency of action on alcohol intake and that its salutary effects on drinking persist after the drug is terminated. Finally, the hypothesis that L-type calcium channel agonists may be useful as a therapeutic adjunct in the treatment of alcoholism is extended.
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  • 61
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    Psychopharmacology 142 (1999), S. 302-308 
    ISSN: 1432-2072
    Keywords: Key words Alcohol ; Beer ; Craving ; Rat ; Naloxone ; SR 141716 ; Ritanserin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were given two weeks of home cage access to either “near-beer” (a beverage that tastes like beer but contains 〈0.5% ethanol v/v) or near-beer with added ethanol (4.5% v/v), which is simply referred to as “beer”. The two groups of rats (near-beer and beer) were then trained on a “lick-based progressive ratio paradigm” in operant chambers in which an ever increasing number of licks had to be emitted for each successive fixed unit of near-beer or beer delivered. Break points (the ratio at which responding ceased) for near-beer and beer were approximately equal under baseline conditions. Rats were then tested for the effects of the 5HT2A/2C receptor antagonist ritanserin (0.625, 2.5 or 10 mg/kg), the opioid receptor antagonist naloxone (0.625, 2.5 or 10 mg/kg) or the cannabinoid CB1 receptor antagonist SR 141716 (0.3, 1 or 3 mg/kg). All three drugs caused a dose-dependent reduction of break-points and locomotor activity in both the beer and near-beer groups. However, the effects of SR 141716 and naloxone, but not ritanserin, on break-points were significantly more pronounced on rats drinking beer compared to those drinking near-beer. There were no such differential effects of any of the drugs on locomotor activity across the two groups. These results suggest that both SR 141716 and naloxone differentially affect the motivation to consume alcoholic beverages and may thus have potential as drugs for the treatment of alcohol craving.
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  • 62
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Midazolam ; Caffeine ; Cocaine ; Amphetamine ; Pentobarbitone ; Ethanol ; Drug discrimination ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Studies of the discriminative stimulus effects of drug mixtures provide an approach to polydrug abuse and studies on single drugs with multiple effects. Objective: This study was designed to investigate whether the use of the AND-OR procedure increases the specificity of drug mixture discriminations. Methods: Rats were trained to discriminate a mixture of amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) from saline (AND-discrimination, n = 8) or to discriminate the same mixture from its component drugs alone (AND–OR discrimination, n = 9). The studies used two-lever operant procedures with a tandem variable interval 1-min fixed ratio 10 schedule of food reinforcement. Results: Under AND-discrimination conditions, there was partial generalization to nicotine and midazolam when each drug was administered singly, and there was no generalization to cocaine, caffeine or ethanol. With the AND-OR discrimination, there was no generalization to any of the preceding drugs administered singly. In “single substitution” tests, nicotine or midazolam was co-administered with the training doses of pentobarbitone and amphetamine, respectively; there was full generalization in the AND-discrimination and partial generalization under AND-OR conditions. Cocaine co-administered with pentobarbitone generalized fully under both procedures, but the dose of cocaine needed was much larger in the AND-OR than in the AND-discrimination. In “dual substitution” tests, mixtures of two novel substances were tested. Mixtures of either nicotine plus midazolam or caffeine plus ethanol produced very marked generalization under AND-discrimination conditions, but were without significant effect in the AND-OR procedure. Throughout the studies, in every instance where comparisons were made, generalization was greater or occurred at lower doses under AND- than under the AND-OR discrimination. Conclusions: The study yielded extensive evidence supporting the hypothesis that the AND-OR discrimination procedure increases the specificity of discriminations based on drug mixtures.
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  • 63
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Mecamylamine ; Tolerance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation.
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  • 64
    ISSN: 1432-2072
    Keywords: Key words Amphetamine ; Behavioral sensitization ; MK-801 ; NMDA receptor ; State-dependency ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Many laboratories have reported that coadministration of N-methyl-d-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative ”state-dependency” interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the ”state-dependency” hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.
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  • 65
    ISSN: 1432-2072
    Keywords: Key words SSRI ; Cytochrome P450 ; Serotonin ; Microdialysis ; Norfluoxetine ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.
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  • 66
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    Psychopharmacology 144 (1999), S. 77-82 
    ISSN: 1432-2072
    Keywords: Key words Acquisition ; Cocaine ; Heroin ; Rat ; Self-administration ; Sex difference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Despite numerous reports that male and female animals differ in behavioral responses to drugs, few studies have investigated sex differences in drug-reinforced behavior. Objectives: Acquisition of IV cocaine and heroin self-administration was compared in 20 female and 22 male Wistar rats. Methods: An autoshaping procedure was used to train rats to press a lever that resulted in either a 0.2 mg/kg infusion of cocaine or a 0.015 mg/kg infusion of heroin under a fixed-ratio 1 (FR 1) schedule. Daily sessions consisted of six 1-h autoshaping components followed by a 6-h self-administration component. During each autoshaping component, a retractable lever briefly (15 s) extended into the test chamber on a random interval schedule with a mean of either 90 s (cocaine groups) or 480 s (heroin groups) and either ten (cocaine groups) or five (heroin groups) computer-automated infusions were delivered each hour. During each 6-h self-administration component, the lever remained extended and each response on the lever resulted in an infusion of either cocaine (0.2 mg/kg) or heroin (0.015 mg/kg). The criterion for acquisition of cocaine self-administration was a mean of at least 100 infusions and the criterion for heroin self-administration was a mean of at least 20 infusions during the self-administration component over five consecutive sessions. Results: Female rats acquired both cocaine and heroin self-administration more rapidly than males. Acquisition of cocaine self-administration occurred in a greater percentage of female rats compared to males. Female rats self-administered more cocaine than males after acquisition criteria had been met. Conclusions: These findings indicate that female rats were more vulnerable than males to the acquisition of cocaine and heroin self-administration under the conditions of the present experiment.
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  • 67
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    Psychopharmacology 144 (1999), S. 111-120 
    ISSN: 1432-2072
    Keywords: Key words Heroin ; Self-administration ; Dependence ; Naloxone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Non-dependent and dependent opiate users appear to be driven by two distinct motivational factors: the primary reinforcing properties of the drug, and the negative reinforcing effects associated with relieving the negative affective component of opiate withdrawal in the dependent state. Objective: To investigate the motivational significance of opioid dependence on heroin self-administration (HSA) in rodents. Methods: Rats were trained to self-administer heroin intravenously (0.06 mg/kg per infusion; FR1), and opiate dependence was induced by subcutaneous implantation of two morphine (75 mg base) pellets.Rats in a non-dependent control group received placebo pellets. Three days after pellet implantation, HSA was resumed in daily 3-h sessions until baseline criteria were met and testing was conducted with subcutaneous injections of vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session. Results: Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet-implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a second experiment, the HSA session was shortened to 1 h and the training dose reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo pellet-implanted rats was increased only following the highest dose of the antagonist, while dependent rats were still affected by naloxone doses of 0.003–0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3), breaking point values in dependent animals were 198% above baseline. Conclusions: The present study supports the hypothesis that dependence-induction by morphine-pellet implant in rats resulted in increased sensitivity to very small naloxone doses, as measured by changes in HSA. Taken together, these data suggest that opiate dependence, as measured by changes in sensitivity to naloxone, is a continuum which can contribute to the motivational state of drug-seeking.
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  • 68
    ISSN: 1432-2072
    Keywords: Key words Schizophrenia ; Extrapyramidal side-effect ; Neuroleptic ; Antipsychotic ; Dopamine D2 receptor ; Serotonin 5-HT1A receptor ; Intrinsic activity ; Paw test ; Catalepsy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Combining neuroleptics with 5-HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role of intrinsic activity at 5-HT1A receptors in the modulatory effects of 5-HT1A ligands, and 3) the generality of the interactions across neuroleptics. Methods: The effects of different doses of 5-HT1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy. Results: Firstly, the 5-HT1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly, neither the weak 5-HT1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently differed in their sensitivity to interactions with 5-HT1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than those of haloperidol or risperidone. Conclusions: The present data suggest that 5-HT1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics. Together with results of previous studies, it appears that 5-HT1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied.
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  • 69
    ISSN: 1432-2072
    Keywords: Key words Delayed non-matching to position task ; Scopolamine ; ENA 713 ; Exelon ; Working memory ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: The disruption of working memory in the delayed non-matching to position (DNMTP) task by the muscarinic antagonist, scopolamine, is considered to be a model of the spatial working memory deficit in Alzheimer’s disease (AD) patients. Objective: To investigate whether ENA 713 (Exelon) (0.1, 0.5 mg/kg, IP), an acetylcholinesterase inhibitor, would reverse the effects of scopolamine in the DNMTP task. Methods: Male Lister Hooded rats were trained to criterion in an operant DNMTP task (0- to 16-s delay intervals) before receiving vehicle, scopolamine (0.05 mg/kg, SC) alone, ENA 713 (0.1, 0.5 mg/kg, IP) alone, or combinations of scopolamine and ENA 713, in two variations of the task – with and without barriers inserted between the food magazine and the two levers. Barriers were inserted to prevent the use of positional strategies to perform the task, since this behaviour may confound the conclusions of the effect of drugs on working memory. Results: It was found that: (i) scopolamine significantly reduced choice accuracy delay-dependently in both test situations while modifying non-mnemonic measures of task performance delay-independently, indicating an impairment of working memory; (ii) ENA 713 (0.5 mg/kg) significantly attenuated the scopolamine-induced impairment of working memory and significantly reduced the scopolamine-induced changes in some non-mnemonic measures of task performance; (iii) the presence of barriers did not alter the effects of scopolamine and ENA 713 on working memory. Conclusion: ENA 713 reversed the working memory deficit induced by scopolamine. These results are consistent with the attenuation of learning and memory disruptions due to cholinergic dysfunction by ENA 713 in other preclinical assays, and predict a drug-induced improvement in working memory in AD patients.
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  • 70
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    Psychopharmacology 146 (1999), S. 19-23 
    ISSN: 1432-2072
    Keywords: Key words Serotonin ; Sensitization ; Rat ; Dopamine opiate ; Movement disorder
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Repeated high doses of morphine in the rat cause stereotypic gnawing behavior that can be re-expressed by a low dose of morphine weeks and even months after the initial treatment. The determination of the role of serotonin in this sensitized morphine-induced behavior has both empirical and theoretical relevance. Objectives: To determine whether the serotonin-reuptake blocker fluoxetine will block the development and/or the expression of this opiate-induced stereotypy. Methods: Rats were given four 10-mg/kg injections of morphine alone or with 5.0 mg/kg fluoxetine over a 36-h period. At weekly intervals for 6 weeks after the last of the sensitizing morphine doses, all rats were challenged with 4.0 mg/kg morphine. At week 2 and week 4, however, the morphine was co-administered with fluoxetine. Results: Fluoxetine completely blocked the expression of the morphine-induced stereotypy; however, when the morphine/fluoxetine-treated rats were challenged with morphine alone, they expressed similar degrees of stereotypy as the rats that initially only received morphine. Conclusions: The results indicate that increasing synaptic serotonin will block the expression but not the development of sensitization to the oral stereotypic effects of repeated high doses of morphine. Also, despite the complete blocking of the morphine effect by fluoxetine during the sensitization phase, the presence of significant biting by these rats during the challenge with morphine alone argues that conditioning factors are not a necessary component for the morphine sensitization to develop.
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  • 71
    ISSN: 1432-2072
    Keywords: Key words Dextromethorphan ; Dextrorphan ; Phencyclidine ; Self-administration ; Drug discrimination ; Monkey ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-d-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models. Objectives and methods: The discriminative stimulus properties of DXO and DXM were tested in rats (3–56 mg/kg DXM, i.p. and 2.2–40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3–10 mg/kg DXM, i.m. and 0.25–8.0 mg/kg DXO, i.m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10–100 µg/kg/infusion) and DXM (10–1000 µg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions. Results: In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects. Conclusions: Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO.
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  • 72
    ISSN: 1432-2072
    Keywords: Key words Amphetamine ; Fluoxetine ; Intracranial self-stimulation thresholds ; Withdrawal ; Depression ; Selective serotonin reuptake inhibitors ; Psychostimulant ; Reward ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized. Objectives: The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs. Methods: A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle. Results: Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1–5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretreatment did not. Amphetamine-induced decreases in response latency, a measure of motor performance, were not affected by either chronic or acute fluoxetine pretreatment. Conclusions: The results of these experiments suggest that chronic fluoxetine treatment may induce adaptive changes in serotonergic transmission that, in themselves, do not alter the function of central reward processes, but may alter the ability of amphetamine to potentiate ICSS reward. In addition, the lack of change in ICSS thresholds during withdrawal from the chronic fluoxetine treatment regimen used suggests that withdrawal from all mood-altering drugs may not necessarily produce changes in central reward functions.
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  • 73
    ISSN: 1432-2072
    Keywords: Key words Ethanol ; Initiation ; Sucrose-substitution ; Appetitive-consummatory ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The concepts of appetitive and consummatory behaviors provide a framework for examining ethanol-drinking behavior. However, traditional studies of ethanol self-administration using dipper procedures make separating the appetitive from the consummatory components difficult. Objective: This study compared the ability to initiate ethanol self-administration using a new sipper-tube self-administration procedure with the older established sucrose-substitution initiation model that employed dipper presented reinforcement. The new model was developed to allow for an assessment of the appetitive and consummatory components in ethanol self-administration. Methods: For the sipper-tube procedure, the rats were initiated to self-administer ethanol using a sucrose-substitution procedure that provided limited access to a sipper tube containing ethanol. This procedure required the completion of a fixed ratio requirement (FR4) in order to gain access to a sipper tube for 20 min. Initially, a 20% sucrose solution with no ethanol was provided in the sipper tube. Over sessions, the concentration of sucrose was reduced and the ethanol concentration increased, until 10% ethanol in water was the solution presented. A second group of animals was initiated to self-administer ethanol using the dipper-presentation procedure employed in our laboratory for many years. This group was used for comparison of the effectiveness of initiation in the sipper-tube procedure. Results: Following initiation, the sipper-tube rats self-administered 10% ethanol in water with intakes averaging 0.75 g/kg during the 20-min drinking period. Increasing the ethanol concentrations as high as 20%, increased intakes as high as 1.5 g/kg. The ethanol intakes observed were similar to those obtained with the dipper initiation procedure but occurred in one-third of the time. Conclusions: The sipper-tube procedure employed here results in similar ethanol self-administration behavior as has been found with a dipper presentation procedure. More importantly, however, it allows for a separation of the appetitive and consummatory components of ethanol self-administration. This separation may prove useful for examining the strength of ethanol-seeking behaviors without the confound of increasing levels of ethanol interacting with the appetitive seeking behaviors.
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  • 74
    ISSN: 1432-2072
    Keywords: Key words Deramciclane ; Ritanserin ; Chlordiazepoxide ; Slow wave sleep ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of serotonergic and benzodiazepine type anxiolytic drugs on the cortical activation and sleep-wakefulness cycle were compared by evaluating the effects of ritanserin and deramciclane (EGIS-3886), two 5-HT2 receptor antagonists, and chlordiazepoxide on the electroencephalogram (EEG) in freely moving rats. Following drug administration (1, 3, and 10 mg/kg, PO for all drugs), EEG was continuously sampled for 6 h and power spectra were calculated for every 5 s to assess changes in slow wave activity and sleep phases. In a separate test, anticonvulsant effects of the drugs were examined in mice. Both deramciclane and ritanserin slightly increased total time spent in deep sleep (DS) and lengthened sleep episodes. In contrast, chlordiazepoxide had a strong inhibitory action on DS, sleep time being shifted to more superficial light sleep (LS). The incidence and length of the high voltage spindle (HVS) episodes characteristic for the motionless, awake rat were increased at the highest dose of both deramciclane and ritanserin, while it was decreased by chlordiazepoxide. In mice, chlordiazepoxide had a marked anticonvulsant effect, while deramciclane was moderately effective and ritanserin ineffective. In conclusion, the 5-HT2 receptor antagonist anxiolytic drugs seem to be superior compared to the benzodiazepine type anxiolytic drug, chlordiazepoxide, as ritanserin and deramciclane improved sleep quality by increasing sleep episode length and time spent in DS, while chlordiazepoxide enhanced sleep fragmentation and decreased DS.
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  • 75
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    Psychopharmacology 142 (1999), S. 327-333 
    ISSN: 1432-2072
    Keywords: Key words Caffeine ; Nicotine self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150–180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking.
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  • 76
    ISSN: 1432-2072
    Keywords: Key words Continuous cocaine ; Tolerance ; 5-HT3 receptor ; DA release ; Nucleus accumbens ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously reported that continuous cocaine administration functionally down regulates 5-HT3 receptors in the nucleus accumbens. The current experiments evaluated the duration of behavioral tolerance to cocaine and whether the duration of behavioral tolerance and 5-HT3 receptor down-regulation co-varied. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-stimulated DA release on days 1 and 7, but not day 14, of withdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withdrawal. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and this functional down-regulation co-varies with the behavioral tolerance induced by continuous cocaine administration. Hence, a functional down-regulation of accumbens 5-HT3 receptors may represent a partial mechanism for the tolerance following continuous cocaine administration.
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  • 77
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    Psychopharmacology 142 (1999), S. 369-374 
    ISSN: 1432-2072
    Keywords: Key words Clozapine ; Withdrawal ; Dependence ; Temperature ; Atypical antipsychotic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment. Objective: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures. Methods: Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study. Results: Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal. Conclusions: Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs.
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  • 78
    ISSN: 1432-2072
    Keywords: Key words Antinociception ; Butorphanol ; Relative efficacy ; Opioid ; Rat ; Stimulus intensity ; Tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. Objective: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. Methods: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50°C (low temperature) and 55°C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (–)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. Results: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (–)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (–)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. Conclusions: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.
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  • 79
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    Psychopharmacology 143 (1999), S. 293-301 
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Drug discrimination ; Norepinephrine ; Desipramine ; Nisoxetine ; Isoproterenol ; Propranolol ; Methoxamine ; Prazosin ; Clonidine ; Yohimbine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale:Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine. Objective:The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine. Methods:In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested. Results: Desipramine (3.0–18.0 mg/kg) and nisoxetine (5.6–30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56–3.0 mg/kg), and antagonist, propranolol (1.0–18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha-1 NE agonist methoxamine (1.0–5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8–10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1–0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56–1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6–10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1–0.3 mg/kg doses of methamphetamine. Conclusions:The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha-1 receptors and beta receptors.
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  • 80
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    Psychopharmacology 143 (1999), S. 315-317 
    ISSN: 1432-2072
    Keywords: Key words SR141716 ; Hyperphagia ; Rat ; Pre-feed ; Eating ; Appetite
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as Δ9-THC, and hypophagic effects of selective cannabinoid receptor antagonists. Objective: This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors. Methods: Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food intake tests. In a second series of intake tests (n=8), anandamide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC). Results: All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by SR141716 pretreatment. Conclusion: This first demonstration of anandamide-induced, CB1-mediated, overeating provides important evidence for the involvement of a central cannabinoid system in the normal control of eating.
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  • 81
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Dopamine ; Serotonin ; Phentermine ; Fenfluramine ; Drug-discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To analyze the involvement of dopamine (DA) and serotonin (5-HT) release in the stimulus properties of methamphetamine, two amphetamine analogs that selectively release either brain DA (phentermine) or 5-HT (fenfluramine) were tested for their ability to substitute for methamphetamine in rats discriminating methamphetamine (1.0 mg/kg) from saline. They were subsequently tested for their ability to alter IV methamphetamine (0.06 mg/kg per injection) self-administration in the same species when given as a pretreatment. The DA releaser phentermine, like methamphetamine itself, decreased methamphetamine self-administration (to 70% of baseline responding), but only at a dose of 3.0 mg/kg that fully generalized to the methamphetamine stimulus in the discrimination study. The 5-HT releaser fenfluramine attenuated methamphetamine self-administration to a much larger extent than phentermine (to 37% of baseline responding) at a dose of 1.8 mg/kg that did not generalize to methamphetamine and did not decrease rate of responding in the discrimination study. Tolerance developed to the inhibitory effect of 1.8 mg/kg fenfluramine on methamphetamine self-administration when it was given repeatedly over four consecutive daily sessions. The fenfluramine-induced decrease in methamphetamine self-administration was also attenuated when it was given together with the small 1.0 mg/kg dose of phentermine. These results suggest that DA release plays a dominant role in the discriminative stimulus effects of methamphetamine. However, stimulation of 5-HT release can strongly modify methamphetamine self-administration.
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  • 82
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Medial geniculate body ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABAB receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABAA receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission.
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  • 83
    ISSN: 1432-2072
    Keywords: Key words Nicotinic acetylcholine receptor ; ABT-418 ; Methylphenidate ; Basal forebrain ; 192 IgG-saporin ; Sustained attention ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Loss of telencephalic cholinergic projections has been postulated to contribute significantly to the cognitive decline associated with aging and dementia. Objective: The effects of the nicotinic acetylcholine receptor agonist ABT-418, a potential therapeutic drug for the treatment of the age- and dementia-associated cognitive disorders, were tested in an animal model of the cortical cholinergic deafferentation-induced impairments in sustained attention. Methods: Animals were trained in an operant task designed to test sustained attention performance. A partial loss of cortical cholinergic inputs was produced by infusions of 192 IgG-saporin into the basal forebrain. The effects of the systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. Results: Compared with sham-lesioned animals, this lesion resulted in a decrease in the relative number of hits while the relative number of correct rejections remained unaffected. Administration of ABT-418 significantly improved the relative number of hits. Furthermore, this effect of ABT-418 interacted with the effects of the lesion. Unexpectedly, this interaction was based on a significant enhancement of the performance of sham-lesioned animals while no effects were found in 192 IgG-saporin-lesioned animals. Administration of methylphenidate did not affect performance. Conclusions: While these data do not support the hypothesis that administration of ABT-418 attenuates the impairments in attentional performance that result from loss of cortical cholinergic inputs, they support previous notions about this drug’s ability to enhance cognitive processes in intact subjects.
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  • 84
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    Psychopharmacology 144 (1999), S. 213-219 
    ISSN: 1432-2072
    Keywords: Key words Alcohol ; Self-administration ; Animal model ; Behavioral economics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: For the purpose of investigating the determinants of preference for alcohol, it would be advantageous to use a procedure in which the subjects had concurrent access to alcohol and an isocaloric food. However, in widely used animal models, the introduction of a weak sucrose solution markedly reduced alcohol consumption. In contrast, when alcohol was sweetened, rats defended high baseline levels of alcohol intake despite access to chow, 10% sucrose, and increases in body weight that markedly reduced food consumption. Under these conditions, certain pharmacological treatments selectively reduced alcohol consumption. The present experiment further tests the generality of the contrast between food and sweetened alcohol consumption in rats. Objective: To test if rats will defend baseline levels of alcohol consumption when (1) the competing reinforcer is an isocaloric, preferred food and (2) when the cost of defending alcohol entails a decrease in food consumption as well as an increase in response output. Methods: The rats had access to a 10% alcohol plus 0.25% saccharin solution and an isocaloric, 14.8% Polycose solution in a two-lever, choice procedure. In the initial condition, the response requirement for each drink was set at five responses (variable-ratio 5); in subsequent conditions the variable-ratio values were increased to 7.5, 10, 15, and 30 responses. Results: In the initial condition, the rats drank twice as much Polycose as alcohol. However, with increases in the variable-ratio requirements, Polycose consumption systematically decreased, whereas sweetened alcohol consumption remained at its baseline level or above in all but the variable-ratio 30 condition. Conclusions: Rats defended baseline alcohol consumption but not baseline food consumption. As alcohol and food consumption can be dissociated in humans, research on the mechanisms that mediate alcohol regulated preference in rats may shed light on the mechanisms that control human alcohol consumption.
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  • 85
    ISSN: 1432-2072
    Keywords: Key words Locomotion ; Activity ; Dose-response ; Time-course ; Anticholinergic drug ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. Objective: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. Methods: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. Results: Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2–6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2–3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. Conclusions: Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine 〉 trihexyphenidyl 〉 biperiden 〉 azaprophen 〉 procyclidine 〉 benactyzine 〉 atropine 〉 aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.
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    Urological research 27 (1999), S. 174-179 
    ISSN: 1434-0879
    Keywords: Key words Apoptosis ; Ischemia-reperfusion ; Blood flow ; Ischemia ; Prostate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanisms involved in the castration-induced involution of the ventral prostate (VP) are not fully understood. It was recently reported that castration decreases blood flow in the VP in rats and that this occurs before the apoptotic involution of the organ. However, it is unknown whether a decrease in blood flow may trigger apoptosis in the VP, and this was therefore examined in this study. The right iliac artery was clamped for 1 h in adult male rats. After 24 h of reperfusion, the VPs were frozen or fixed. In situ end-labeling (ISEL) was used to identify apoptotic cells, and testosterone repressed prostatic message-2 (TRPM-2) was measured. Proliferating cell nuclear antigen (PCNA) immunohistochemistry was used to identify proliferating cells. Clamping the right iliac artery reduced blood flow in the right VP to 0.17 of that in the contralateral lobe. This relative ischemia resulted in a threefold increase in the volume density of apoptotic epithelial cells on the treated side, but left cell proliferation unaffected. Testosterone substitution did not change this pattern. This study suggests that a transient period of relative ischemia may induce apoptosis in the rat ventral prostate. This may be of importance for the understanding of castration-induced prostatic involution.
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  • 87
    ISSN: 1434-0879
    Keywords: Key words Nonbacterial prostatitis ; Animal model ; Partial urethral obstruction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pathogenesis of nonbacterial prostatitis (NBP) is not understood mainly due to the lack of appropriate experimental models. We developed a new experimental model of NBP by inducing a partial obstruction of the urethra (PUO) in the rat. Male Wistar rats aged 12 weeks were used. PUO was produced by a nylon ligature on the urethra over a rubber tube. The tube was slipped out after the ligature had been tied. Two rats were examined histologically 6 h, 1 day, 3 days and 7 days after PUO. In another group, two rats were killed at 1, 3 and 7 days after the release of the PUO that had been left in place for 3 days. On day 3, another eight rats with PUO and eight control rats had 2 ml of urine in the bladder replaced by the same volume of lucifer yellow (LY; 10 μg/ml, MW 500), microperoxidase (MP; 20 μg/ml, MW 1900), horseradish peroxidase (HRP; 10 μg/ml, MW 40 000), or saline as control, respectively. Lymphocytic infiltration and interstitial edema were noted in the prostate following PUO, being most prominent on day 3. After the release of the PUO, these inflammatory changes gradually disappeared. Only LY was noted within the prostatic stroma of the rats 2 h after bladder instillation. Intraprostatic urinary reflux may be an etiologic factor in NBP. The present study showed that lower urinary tract obstruction caused NBP in the rat. Penetration of prostatic tissue by low-molecular-weight substances in the urine may trigger NBP.
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  • 88
    Electronic Resource
    Electronic Resource
    Springer
    Urological research 27 (1999), S. 41-47 
    ISSN: 1434-0879
    Keywords: Key words Ureter ; Histology ; Polyuria ; Diabetes mellitus ; Nephrectomy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of increased functional load on the macroscopical and histological appearance of the ureter was investigated. Sixty rats were divided into five groups: (1) sucrose-fed rats with non-osmotic polyuria; (2) diabetic rats with osmotic polyuria; (3) uninephrectomized rats; (4) sham-operated control rats; and (5) control rats. The 24-hour urinary volume was measured on days 7, 14 and 21. Growth of the kidney, ureter and bladder was investigated and the histological appearance of the ureter was further evaluated. Diabetic and sucrose-fed rats had comparable polyuria with a seven-fold increase in urinary output. The urinary volume for the remaining kidney was doubled in uninephrectomized rats. After 3 weeks, diabetic rats had increased weight of the kidney, ureter and bladder, sucrose-fed rats had increased weight of the bladder, whereas uninephrectomized rats had increased weight of the kidney and ureter. The cross-sectional area (CSA) of the ureter wall from control rats increased from the proximal to the distal portion. The size of the whole ureter from diabetic rats was dramatically increased, the CSA of the wall of the distal ureter portion being four times that of the controls. The CSA of the ureter wall from sucrose-fed rats was increased only in the distal portion, whereas the ureter from uninephrectomized rats was increased only in the proximal portion. The results demonstrate the importance of differentiating between different portions of the rat ureter when examining histological sections of this organ. Moreover, polyuria per se is shown to induce growth of the bladder and of the adjacent distal part of the ureter, whereas uninephrectomy and diabetes caused growth of the kidney and the upper parts of the ureter, in addition to the growth induced by polyuria.
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  • 89
    Electronic Resource
    Electronic Resource
    Springer
    Urological research 27 (1999), S. 476-482 
    ISSN: 1434-0879
    Keywords: Key words Urinary bladder ; Enterocystoplasty ; Cecocystoplasty ; Innervation ; Nerve growth ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Incorporation of bowel into the bladder (enterocystoplasty) has been widely used to increase bladder capacity. It has been reported by others that the response of smooth muscle from the cystoplastic segment of the intestine shifts from that of the intestine (relaxation to α-agonists and ATP) to that of the bladder (contraction to α-agonists and ATP). This suggests a functional integration of the intestinal muscle into the bladder; the mechanisms are unknown. The aims of the present study were (1) to elucidate if there are signs of bladder nerves sprouting across the anastomosis into the intestinal segment, and (2) to study what happens with the intrinsic innervation of the intestinal segment. As a model, we used cecocystoplasty in rats. The bladder was opened and a patch of cecum with intact vascular supply was anastomosed to the bladder. After two to 11 months the rats were sacrificed and the bladders mounted as wholemounts and stained for acetylcholinesterase-containing nerves, or embedded in paraffin for histology. A pronounced degeneration of the myenteric plexus was found in the cecal segments. In some areas, this had proceeded to the extent that the ganglia were isolated ovoid lumps of cells with no apparent connection to other ganglia. Areas lacking ganglia and nerve trunks but still with muscle could be found in all specimens. Abundant axon bundles were demonstrated sprouting from the cut bladder nerves close to the anastomosis. The bundles spread out in a fan-like pattern or were organized as fewer thicker nerves. There were many nerve bundles entering the cecal segment where they branched and the diameter decreased till they no longer became visible. Some nerves reached surviving lumps of myenteric ganglion cells. The results show that the bladder nerves sprout into the anastomosed cecal segment. It is reasonable to assume that these nerves are responsible for the changes in receptor pharmacological properties of the cecal smooth muscle towards that of bladder muscle.
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  • 90
    Electronic Resource
    Electronic Resource
    Springer
    European archives of oto-rhino-laryngology and head & neck 256 (1999), S. S38 
    ISSN: 1434-4726
    Keywords: Key words Taste buds ; Cytochalasin D ; Rhodamine-phalloidin ; Confocal laser microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Effects of cytochalasin D on actin filaments in cells encircling taste pores were examined to clarify the functional role of actin filaments in the maintenance of taste pores in rat fungiform papillae, using a confocal laser microscope and a scanning electron microscope. Fluorescence in the taste pore cells was detected as a ring shape produced by actin staining with rhodamine-phalloidin. Treatment of fungiform papillae with cytochalasin D diminished the positive reactions in the taste pore cells and increased the inner diameter of the ring reactions. However, deformation of the taste pores in fungiform papillae was not detected under a scanning electron microscope after treatment with cytochalasin D. These findings suggest that the organization of actin filaments encircling the taste pores contributes to regulation of the taste pore’s size in rat fungiform papillae.
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  • 91
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    European archives of oto-rhino-laryngology and head & neck 256 (1999), S. 442-444 
    ISSN: 1434-4726
    Keywords: Key words Wheat germ agglutinin-conjugated ; horseradish peroxidase ; Neural regeneration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Regeneration of the mammalian central vestibular system was examined in rat. The lateral vestibulospinal tract (LVST) of infant rat was transected unilaterally at the level of C1–3. After a postoperative interval of several weeks, the LVST was examined by injecting an anterograde tracer (wheat germ agglutinin-conjugated horseradish peroxidase) into the lateral vestibular nucleus (LVN) and a retrograde tracer (Fast Blue) into the lumbar enlargement. More than half of the rats showed successful regeneration, indicating definite plasticity in the mammalian central vestibular system.
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  • 92
    ISSN: 1432-2277
    Keywords: Key words Xenotransplantation ; 15-deoxyspergualin ; Guinea pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study aimed to investigate the effects of 15-deoxyspergualin (DSG), tacrolimus (FK 506) and cyclosporin A (CyA), alone or in combination, on delayed xenograft rejection (DXR). We used the guinea-pig-to-C6-deficient (C6–)-PVG-rat heart transplantation model, since in this strain combination, hyperacute rejection is avoided. In C6- control rats, the guinea pig xenografts survived for 39.2 ± 6.3 h (mean ± SD). Splenectomy alone resulted in a xenograft survival of 71.8 ± 7.8 h, but the addition of CyA or FK 506 did not further improve graft survival (73.6 ± 3.0 h and 72.0 ± 17.6 h, respectively). In contrast, DSG treatment increased graft survival to a mean of 99.8 ± 9.2 h. When CyA or FK 506 was combined with DSG, no additional effects were observed (105 ± 24.3 h and 95.1 ± 5.6 h, respectively). DSG alone or in combination with FK 506 or CyA resulted in a significant reduction in the serum IgM levels and reduced the deposits of IgM and IgG in rejected grafts. However, all xenografts were still heavily infiltrated by ED1 + macrophages, regardless of the treatment used. Thus, DSG treatment resulted in moderate prolongation of xenograft survival in C6– rats. The effect seems to be related to suppression of xenoreactive antibody production. To prolong xenograft survival further, strategies that inhibit macrophage infiltration seem required.
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  • 93
    ISSN: 1432-5233
    Keywords: Key words Cadmium ; Diabetes ; VEP ; TBARS ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty-two healthy male Swiss albino rats, aged three months, were used in this study. They were divided into four groups: control (c), diabetic (D), cadmium (Cd), and diabetic + Cd (D+Cd). A diabetic condition was induced in D and D + Cd groups by administration of alloxane (5 mg/100 g). After this treatment, Cd and D + Cd groups were injected intraperitoneally with CdCl2 (2 mg/kg week). At the end of the 2-month experimental period, flash visual evoked potentials (FVEPs) of the four groups were recorded with disk electrodes attached with electrode paste 0.5 cm in front of and behind the bregma. The mean latencies off the P1, N1, P2, N2 and P3 components were significantly prolonged in the diabetic group compared with the control group. The mean latencies of P3 in the D + Cd group and of P1 and P3 in the Cd group were longer than those of the control group. P2N2 amplitude of Cd and D + Cd groups were significantly increased compared with the control group. On the other hand, thiobarbituric acid-reactive substances (TBARS) were determined as an indicator of lipid peroxidation. Our data showed that Cd treatment and diabetic condition caused a significant increase of lipid peroxidation in kidney, brain, retina and lens.
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  • 94
    ISSN: 1432-2072
    Keywords: Key words 7-OH-DPAT ; d-Amphetamine ; Dopamine ; Extinction ; Haloperidol ; Progressive-ratio ; Rat ; Self-stimulation ; Ventral tegmental area
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Progressive-ratio (PR) schedules, which have been widely used to study the reinforcing efficacy of various reinforcers (in particular IV psychostimulants), have been very seldom applied to the study of positively reinforcing electrical brain stimulation (EBS). In the present study, rats were required to emit a progressively increasing number of lever-presses (3,4,6,7,9,11,14,16, etc.) for access to successive reinforcers (periods of VTA self-stimulation). Each period of self-stimulation consisted of ten trains of square pulses of EBS; each train was available under a continuous reinforcement schedule. The number of periods of EBS earned during a session was deemed the breaking point (BP). After acquisition and stabilization of self-stimulation, a study was carried out to verify that changes in the strength of the EBS (i.e. changes in the frequency, the intensity or the pulse duration, one parameter at a time) induced changes in the BP. The effects of IP pretreatments with d-amphetamine, the dopamine D3/D2 receptor agonist 7-OH-DPAT and haloperidol were then assessed. Decreases in the strength of EBS decreased the BP. However, increasing the strength above training values resulted in minimal increases in the BP. d-Amphetamine (0.25–1 mg/kg) dose-dependently increased the BP; additionally, when the reinforcer was withheld (i.e. in conditions of extinction, with the stimulator turned off) d-amphetamine was also found to augment the BP. This might indicate that d-amphetamine preferentially potentiated the motivational (non-rewarded presses) aspects of VTA self-stimulation under this type of PR schedule. 7-OH-DPAT had biphasic effects: at low doses (0.01 and 0.03 mg/kg), it tended to decrease the BP while higher doses (1 and 3 mg/kg) robustly increased the BP. Under conditions of extinction, 7-OH-DPAT (1 mg/kg) had a tendency to increase the BP, but this effect was not statistically significant and did not approach the magnitude of effects observed with d-amphetamine. Haloperidol (0.08–0.48 mg/kg IP) dose-dependently reduced the BP, suggestive of a decrease in the reinforcing efficacy of the EBS. These results show that rats can be trained to self-administer EBS of the VTA under a PR schedule of reinforcement and that this behaviour is sensitive to disruption or potentiation of dopaminergic neurotransmission.
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  • 95
    ISSN: 1432-2072
    Keywords: Key words Neurosteroids ; GABAA receptor ; Sleep ; EEG spectral analysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABAA receptor functioning. To assess the involvement of GABAA receptors, we investigated the sleep responses to one dose of the GABAA antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (≤8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABAA receptors play an important role in the sleep effects of progesterone.
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  • 96
    ISSN: 1432-2072
    Keywords: Key words Ethanol ; Self-administration ; Dopamine ; Acetylcholine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present study, the reactivity of striatal dopamine and dopamine-sensitive neurons in superfused striatal slices of ethanol-experienced rats was compared to that of ethanol-naive rats, 3 weeks after oral ethanol self-administration. During the acquisition phase (17 days), rats were offered increasing concentrations of ethanol (from 2 to 10%, 24 h per day) on an alternate-day schedule in a free choice with water. Following 2 weeks of unrestricted 10% ethanol consumption, the highest and lowest drinkers (representing about 25% of the upper and lower extremes of the total population) were selected. Preliminary experiments revealed that both groups of rats displayed a profound increase in ethanol consumption and preference 3 weeks after cessation of ethanol self-administration (deprivation effect). This deprivation effect was associated with an increase in electrically evoked release of [3H]dopamine from superfused nucleus accumbens slices, whereas the evoked [3H]dopamine release from caudate putamen slices remained unchanged. In slices of the caudate putamen, but not in nucleus accumbens slices, postsynaptic dopamine D1 receptor-stimulated cyclic AMP production was also enhanced. In addition, prior ethanol consumption enhanced the electrically evoked release of [14C]acetylcholine release in both striatal regions. Interestingly, the magnitude of these long-term neuroadaptations correlated with the amount of daily ethanol consumption, i.e. neuronal hyperresponsiveness in the striatum was more profound in the high than in the low ethanol drinkers. These data show for the first time that unrestricted free-choice ethanol consumption in rats is associated with a long-term increase in dopaminergic and cholinergic neurotransmission in the nucleus accumbens and caudate putamen. These (and other) neuroadaptations may underlie the enhanced motivation to self-administer ethanol and the maintenance of ethanol consumption long after deprivation.
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  • 97
    ISSN: 1432-2072
    Keywords: Key words Anhedonia ; Amphetamine ; Depression ; Progressive ratio ; Psychostimulant ; Rat ; Sucrose solution ; Withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Numerous studies have shown that withdrawal from sustained high doses of psychostimulant drugs such as cocaine or d-amphetamine produces depressive-like symptoms in both rats and humans. The majority of experiments with rodents have assessed the effects of amphetamine withdrawal on reinforcing electrical self-stimulation in different brain regions, but relatively few have examined effects on responding for natural reinforcers. In the present study, two groups of mildly food and water deprived male rats were trained to respond on a lever for a 4% sucrose solution under a progressive ratio schedule of reinforcement. One group was subsequently administered a 4-day regimen of injections of increasing doses of d-amphetamine based on a schedule shown previously to reduce self-stimulation behaviour. Break points were significantly reduced for up to 4 days after the termination of drug administration, suggesting a decreased motivation to obtain the natural reward. A further experiment demonstrated that the identical drug regimen produced no effect upon consumption of the 4% sucrose solution when it was freely available. These results demonstrate that the progressive ratio procedure may be a useful technique for evaluating changes in motivation for natural reinforcing stimuli following withdrawal from psychostimulant drugs.
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  • 98
    ISSN: 1432-2072
    Keywords: Key words MDMA (3 ; 4-methylenedioxymethamphetamine) ; Serotonin ; Psychopathology ; Human ; Rat ; Prepulse inhibition ; Habituation ; Schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak prepulse stimulus. This phenomenon provides an operational measure of sensorimotor gating that has been found to be reduced in patients with schizophrenia and rats treated with serotonin agonists or serotonin releasers. Objective: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. Methods: Rats were tested after placebo and MDMA in a counterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test day, rats were first tested after no injections and retested 2 h later, 10 min after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI measures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. Results: As expected, MDMA decreased prepulse inhibition in a dose-related fashion in rats. In contrast, a typical recreational dose of MDMA (1.7 mg/kg, orally) increased prepulse inhibition in subjects experiencing robust psychological effects. Conclusions: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific difference in the mechanism of action of MDMA or in the behavioral expression of a similar pharmacological effect, or both.
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  • 99
    ISSN: 1432-2072
    Keywords: Key words Nicotinic receptor ; Dorsal hippocampus ; Anxiety ; Phobia ; Elevated plus-maze ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (–)-nicotine in the social interaction test. Objective: To determine the effects of a wide dose range of (–)-nicotine on trial 1 and 2 in the plus-maze after systemic administration and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. Methods: (–)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze. Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 μl of artificial CSF or (–)-nicotine (0.1, 1, 4 or 8 μg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial 1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier. Results: Low doses of (–)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses (0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage entries onto the open arms. Infusion of (–)-nicotine (0.1, 1, 4 and 8 μg) bilaterally into the dorsal hippocampus was without effect on trial 1, but 1 μg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms. Conclusions: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2) showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to be identified.
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  • 100
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Nornicotine ; Behavioral sensitization ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Nicotine, a tobacco alkaloid, is known to be important in the acquisition and maintenance of tobacco smoking. Nornicotine, an active nicotine metabolite, stimulates nicotinic receptors and may produce psychomotor effects similar to nicotine. Objective: The present study determined the effects of acute and repeated administration of nornicotine on locomotor activity and compared its effects with those of nicotine. Methods: R(+)-Nornicotine (0.3–10 mg/kg), S(–)-nornicotine (0.3–10 mg/kg), S(–)-nicotine (0.1–1 mg/kg) or saline was administered s.c. to rats acutely or repeatedly (eight injections at 48-h intervals). Activity was recorded for 50 min immediately after each injection. Results: S(–)-Nicotine produced transient hypoactivity, followed by dose-related hyperactivity. Repeated S(–)-nicotine administration resulted in tolerance to the hypoactivity and sensitization to the hyperactivity. Subsequent testing following a saline injection revealed evidence of conditioned hyperactivity. Acute administration of 0.3 mg/kg or 1 mg/kg R(+)- or S(–)-nornicotine produced no effect. Transient hypoactivity was observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(–)-nornicotine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicotine-induced psychomotor effects differ qualitatively from those of S(–)-nicotine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypoactivity, however hyperactivity was not observed. Repeated S(–)-nornicotine resulted in tolerance to the hypoactivity and the appearance of hyperactivity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in response to a 1 mg/kg S(–)-nicotine challenge, suggesting some commonalities in the mechanism of action. Conclusion: Nornicotine likely contributes to the neuropharmacological effects of nicotine and tobacco use.
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