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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 196 (1997), S. 417-426 
    ISSN: 1432-0568
    Keywords: Key words Neuronal plasticity ; Fiber growth ; Regeneration ; Rat ; CNS myelin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  After lesions in the central nervous system (CNS), the affected nerve fibers usually cannot regenerate and reconnect to their original target cells. One important reason for this failure to regenerate is the presence of neurite growth inhibitory molecules in the myelin sheath of central nerve fibers. Despite the absence of regeneration fiber growth can occur after CNS lesions from intact nerve fibers unaffected by the lesion. These fibers can form new collaterals and sprout into the region denervated by the lesion, thereby increasing their terminal arbors in a process called collateral sprouting. A certain functional compensation for the nerve fibers lost by the lesion can be achieved by this mechanism. In the spinal cord, collateral sprouting is extensive after lesions in young postnatal animals and decreases with increasing age. In the spinal cord of adult animals, axon sprouting can be observed but is strongly restricted. The factors that determine the amount of sprouting found after lesions at different ages are still largely unknown. Recent evidence suggests that the myelin-associated neurite growth inhibitors that suppress regeneration also restrict collateral sprouting in the spinal cord. In addition, the expression of growth-associated molecules, in particular the growth-associated protein GAP-43, by the sprouting nerve fibers appears to be an important determinant of the sprouting response. The robustness of the sprouting response is thus likely to be controlled by intrinsic growth determinants of the sprouting neuron as well as by the growth promoting and growth inhibitory properties of the microenvironment of the sprouting fibers.
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  • 2
    ISSN: 1432-1211
    Keywords: Key words Eotaxin ; Chemokine ; Eosinophil ; Lung ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1211
    Keywords: Key words CD4 ; Rat ; LEC ; thid ; Chromosomal mapping
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0738
    Keywords: Key words Thyroid carcinogenesis ; Vitamin A ; Thiourea ; UDP-GT ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.
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  • 5
    ISSN: 1432-0738
    Keywords: Key wordsCo-administration ; Cyclosporin A ; Acyclovir ; Nephrotoxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The immunosuppressive agent cyclosporin A (CyA) and the antiviral drug acyclovir may cause renal functional impairment. CyA-induced immunosuppression increases the rate of viral infections. Therefore we were interested to determine whether short-term co-administration of CyA and acyclovir involves an increased nephrotoxic risk. Male Wistar rats were treated with CyA (20 mg/kg body wt., s.c., once daily for 8 days), acyclovir (15 mg/kg body wt., s.c., 3-times daily for the last 5 days) or a combination of CyA and acyclovir. Blood levels of CyA were determined after a single dose. Urine was monitored for volume, osmolality, total protein and N-acetyl-β-d-glucosaminidase (β-NAG). Concentrations of blood urea nitrogen (BUN) and plasma-creatinine were determined (day 9). Renal cortical slices were monitored for accumulation of weak organic acids (para-aminohippurate, PAH) and bases (tetra-ethylammonium, TEA) and for malondialdehyde (MDA) content. Renal histology was also examined. CyA induced a decrease in body and kidney weight, in urine osmolality and in the excretion of total protein. Plasma-creatinine and BUN as well as MDA content of renal tissues were increased by CyA. Acyclovir alone did not induce significant changes. In comparison to CyA values, urine volume and β-NAG excretion were enhanced and TEA accumulation depressed by the concomitant administration of CyA and acyclovir. CyA- or acyclovir-treatment alone did not result in significant morphological changes. In the group co-administered CyA/acyclovir, the kidneys showed mild to moderate signs of tubulopathy. Short-term co-administration of CyA and acyclovir was concluded to have possibly increased nephrotoxic potential.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 113 (1997), S. 343-352 
    ISSN: 1432-1106
    Keywords: Memory ; Glutamate receptors ; GABA receptors ; Modulatory sites of NMDA receptors ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Effects of redox reagents on excitatory and inhibitory synaptic responses as well as on the bidirectional plasticity of α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) andN-methyl-d-aspartate (NMDA) receptor-mediated synaptic responses were studied in CA1 pyramidal neurons in rat hippocampal slices. The oxidizing agent 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB, 200 μM) did not affect AMPA, GABAA or GABAB receptor-mediated synaptic responses or the activation of presynaptic metabotropic receptors. However, DTNB irreversibly decreased (by approximately 50%) currents evoked by focal application of NMDA. DTNB also decreased the NMDA component of the EPSC. The reversal potential of NMDA currents and the Mg2+ block were not modified. In the presence of physiological concentrations of Mg2+ (1.3 mM), DTNB did not affect the NMDA receptor-dependent induction of long-term potentiation (LTP) or long-term depression (LTD) expressed by AMPA receptors. In contrast, DTNB fully prevented LTP and LTD induced and expressed by NMDA receptors. Plasticity of NMDA receptor-mediated synaptic responses could be reinstated by the reducing agenttris-(2-carboxyethyl) phosphine (TCEP, 200 μM). These results suggest that persistent, bidirectional changes in synaptic currents mediated by NMDA receptors cannot be evoked when these receptors are in an oxidized state, whereas NMDA-dependent LTP and LTD are still expressed by AMPA receptors. Our observations raise the possibility of developing therapeutic agents that would prevent persistent excitotoxic enhancement of NMDA receptor-mediated events without blocking long-term modifications of AMPA receptor-mediated synaptic responses, thought to underlie memory processes.
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  • 7
    ISSN: 1432-1106
    Keywords: Key words Fornix ; Cingulate cortex ; Prefrontal cortex ; Cingulum bundle ; Hippocampus ; Object recognition ; Object location ; Memory ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The first experiment assessed the effects of neurotoxic lesions in either the anterior cingulate cortex (ACc) or the retrosplenial cortex (RSc) on a test of object recognition. Neither lesion affected performance on this task, which takes advantage of the rat’s normal preference to spend more time investigating novel rather than familiar stimuli. In response to this negative result, a second experiment assessed the effects of much more extensive cingulate lesions (Cg) on both object recognition and object location memory. The latter task also used a preference measure, but in this case it concerned preference for a novel location. For comparison purposes this second study included groups of rats with lesions in closely allied regions: the fornix (Fx), the cingulum bundle (CB) and the medial prefrontal cortex (Pfc). Comparisons with sham-operated control rats showed that none of the four groups (Cg, Fx, CB, Pfc) was impaired on the object recognition task, adding further weight to the view that these structures are not necessary for assessing stimulus familiarity. The Fx and Cg groups were, however, impaired on the object location task, suggesting that these regions are necessary for remembering other attributes of a stimulus (spatial location).
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  • 8
    ISSN: 1432-1106
    Keywords: Key words Fascia dentata ; Mossy cells ; Interneurons ; Lucifer yellow ; Phaseolus vulgaris leucoagglutinin ; Septohippocampal projection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Mossy cells in the hilus of the rat dentate gyrus are the main cells of origin of the dentate commissural and associational projections. They project along the septotemporal axis of the dentate gyrus and may thus influence the hippocampal signal flow in a longitudinal direction. To analyze the septal innervation of these hilar neurons, anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHAL) was used in combination with intracellular labeling of mossy cells (Lucifer yellow). Anterogradely labeled septal fibers impinge on proximal and distal dendrites of hilar mossy cells but spare the cell body. In contrast, numerous aspiny hilar neurons, presumably GABAergic interneurons, receive a septal innervation on their somata and proximal primary dendrites. These data demonstrate that septal fibers show a specificity for the dendritic segments of hilar mossy cells. Since mossy cells project predominantly to adjacent hippocampal lamellae, the activity of adjacent portions of the dentate gyrus may be influenced by the septal input onto these neurons.
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  • 9
    ISSN: 1432-1106
    Keywords: Key words Eyeblink reflex ; Orbicularis oculi motoneurons ; Facial motor nucleus ; Confocal imaging ; Retrograde labeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The eyeblink reflex is one of the most extensively studied behaviors in mammals. The active downward force that causes lid closure is controlled by the orbicularis oculi (OO) muscle. To augment our studies on the neurophysiology and plasticity of the rat eyeblink circuit, here we present the first anatomical paper to focus exclusively on identifying and characterizing the OO motoneurons of the rat facial motor nucleus (FMN). One thousand and twenty-nine cells from four animals were retrogradely labeled by injecting the OO muscle with HRP and were imaged conventionally. One hundred and one cells from five animals were labeled by injecting the OO muscle with a 3000 mol. wt. fluorescent dextran and were imaged using confocal laser scanning microscopy (CLSM). The latter method resulted in little tissue shrinkage, bright labeling, and excellent resolution of the soma, dendrites, and axon. Furthermore, it is a histologically simple alternative to HRP for retrograde labeling from the neuromuscular junction. Both methods revealed that the OO motoneurons were distributed over the entire length of the FMN, that they were concentrated along the dorsal crest of the nucleus, and that they were less numerous in the extreme rostral and caudal regions. As measured using the CLSM method, cell body areas were highly variable, ranging from 317 to 1500 μm2, but there was no size gradient along the rostrocaudal extent of the FMN. The neurons exhibited seven primary dendrites on average, which gave rise to bifurcating and even trifurcating secondary dendrites. Using the HRP method, the estimated area of OO motoneurons ranged from 161 to 1381 μm2. The combined methods furnished a detailed characterization of the number, spatial distribution, and morphology of rat OO motoneurons. Moreover, these methods provide a useful way to analyze the circuitry that modulates the rat eyeblink.
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  • 10
    ISSN: 1432-1106
    Keywords: Key words Enkephalin ; GABA ; Basal ganglia ; 6-Hydroxydopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In Parkinson’s disease the dopaminergic nigrostriatal pathway degenerates, resulting in an imbalance in activity of two pathways of information flow through the basal ganglia. In animal models of the disease, the striatonigral pathway becomes underactive and the striatopallidal pathway becomes overactive. In the present study immunocytochemistry for enkephalin and GABA and anterograde labelling were used to investigate whether morphological plasticity occurs in striatopallidal terminals following unilateral removal of the nigrostriatal dopaminergic pathway. Pallidal terminals were immunostained to reveal enkephalin and examined in the electron microscope (n=399). Immunoreactive synaptic bouton profiles were on average 64% larger on the experimental side 26 days after the lesion. Analysis of their shape revealed that those on the dopamine-depleted side of the brain were more irregular in profile and that their synaptic specialisations were more complex in shape but not significantly different in length. Striatopallidal terminals were also identified by GABA immunocytochemistry combined with anterograde labelling (n=20). Double-labelled boutons were significantly larger in cross-sectional area on the experimental side (57%). Analysis of terminals that were simply labelled by the immunogold method to reveal GABA (n=278) showed no significant differences in size between terminals from the dopamine-depleted and control side. This suggests that a substantial number of GABAergic terminals in the globus pallidus do not belong to the striatopallidal population of terminals. These morphological changes correlate with previous studies suggesting striatopallidal boutons are more active after destruction of dopaminergic input to the neostriatum.
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  • 11
    ISSN: 1432-1106
    Keywords: Key words Amino acid immunocytochemistry ; Axon collateralization ; Thalamus ; Fluorescent tracers ; Limbic system ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Small, stereotaxically guided injections of true blue (TB) were made into the retrosplenial granular cortex (RSg) and of diamidino yellow (DY) into the dorsal portion of the rostral pole of the thalamic reticular nucleus (TRN) in 16 adult rats to determine whether axons projecting from the anterior thalamic nuclear complex (ATN) to the TRN are branches of axons also projecting to the RSg. Following injections of the fluorescent dyes, serial coronal sections of the brain revealed single retrogradely labelled, and large numbers of double retrogradely labelled neuronal cell bodies in the ipsilateral anteroventral and anterodorsal nuclei and smaller numbers in the anteromedial nucleus of the ATN complex. In a se- cond series of six adult rats with similar double injections of TB and DY, two sections in three were immunoreacted, one with antiserum against glutamate and one with antiserum against aspartate, using indirect immunofluorescence with rhodamine to detect reactive cells. The great majority of both single and double retrogradely labelled cell bodies were also immunoreactive for aspartate or glutamate. In addition, a moderate to small number of non-immunolabelled neurons projecting to the TRN and/or to the RSg were also found in all three nuclei of the ATN complex. These results are compatible with the possibility that large numbers of neurons in the ATN send axonal branches to both the RSg and the TRN, and that many such neurons use glutamate and/or aspartate as transmitters. The findings also suggest that the projections from the ATN might be heterogeneous with respect to transmitter phenotype.
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 116 (1997), S. 97-103 
    ISSN: 1432-1106
    Keywords: Key words Chronic constriction injury ; Infraorbital nerve ; Painful trigeminal neuropathy ; Heat-hyperalgesia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Secondary trigeminal neuralgia (STN) follows an injury to the trigeminal nerve or one of its branches. Although rare, this condition results in great suffering and it is notoriously difficult to treat. The experimental analysis of painful neuropathy due to damage to the innervation of the limbs (e.g., the sciatic nerve) has progressed rapidly in recent years, but very few reports have appeared concerning experimental neuropathy in the trigemenial region. We report here an experimental rat model of trigeminal neuropathic pain produced by a chronic constriction injury to the infraorbital nerve (CCI-ION), and on a method that detects heat-evoked pain-related behavior. Rats with the CCI-ION have clear signs of heat-hyperalgesia when stimulated on the snout (the vibrissal pad). The hyperalgesia is seen both ipsi- and contralateral to the side of nerve injury, but is significantly more severe ipsilaterally, and lasts about 12 days.
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  • 13
    ISSN: 1432-1106
    Keywords: Key words Perinatal asphyxia ; Apoptosis ; Necrosis ; Hematoxylin-eosin ; DNA fragmentation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The consequences of perinatal asphyxia on the rat brain were studied 80 min to 8 days after birth with hematoxylin-eosin and in situ DNA double-strand-breaks labeling histochemistry. Asphyxia was induced by immersing fetus-containing uterus horns, removed from ready-to-deliver Sprague-Dawley rats, in a water bath at 37°C for various time periods (0–22 min). Spontaneous- and cesarean-delivered pups were used as controls. Perinatal asphyxia led to a decrease in the rate of survival, depending upon the length of the insult. No gross morphological changes could be seen in the brain of either control or asphyctic pups at any of the studied time points after delivery. However, in all groups, nuclear chromatin fragmentation, corresponding to in situ detection of DNA fragmentation, was observed at different stages. Nuclear fragmentation in control pups showed a specific distribution that appeared to be related to brain maturation, thus indicating programmed cell death. A progressive and delayed increase in nuclear fragmentation was found in asphyctic pups, which was dependent upon the length of the perinatal insult. The most evident effect was seen in frontal cortex, striatum, and cerebellum at postnatal day 8, although changes were also found in ventral-posterior thalamus, at days 1 and 2. Thus, nuclear chromatin fragmentation in asphyctic pups indicates a delayed post-asphyctic neuronal death. The absence of signs of inflammation or necrosis suggests that delayed neuronal cell death following perinatal asphyxia is an active, apoptosis-like phenomenon.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 115 (1997), S. 129-136 
    ISSN: 1432-1106
    Keywords: Key words Fos-like immunoreactivity ; Middle cerebral artery ; Focal cerebral ischaemia ; Spinal cord neurons ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This study examined c-fos protein expression in the brain and spinal cord of rats following permanent occlusion of the middle cerebral artery (MCA) above the rhinal fissure. At 1 h after right-sided MCA occlusion, Fos-like immunoreactivity (Fos-LI) was detected in neurons not only in the ipsilateral cerebral cortex but also in the spinal cord. In the latter, Fos-LI was localized in the nucleus and perikarya of neurons in the grey matter, notably the large motor neurons in the ventral horn. Fos-LI was most intense at 2–4 h, but became undetectable after 48 h in the cerebral cortex and 72 h in the spinal cord. In sham-operated animals, Fos-LI was almost undetectable or virtually absent. It was also not detected in the core territory supplied by the MCA at any time points after arterial occlusion. When the ischaemia-induced neuronal damage in both the cerebral cortex and spinal cord was evaluated by Nissl staining, some neurons appeared atrophic. We conclude that the induction of Fos-LI in neurons of the cerebral cortex and spinal cord is linked respectively to early onset–short stimulation and persistent excitatory or disinhibition phenomenon as a result of focal ischaemic brain injury.
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  • 15
    ISSN: 1432-1106
    Keywords: Transplant ; Striatum ; Substantia nigra ; Patch-matrix ; Regeneration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract When patients with Parkinson’s disease initially show symptoms, approximately 80–85% of their dopaminergic nerve fibers in the striatum have degenerated. It is thus of importance to develop strategies to try to rescue the remaining dopaminergic neurons and to stimulate them to induce sprouting. In this study the goal was to examine whether the different subgroups of dopaminergic neurons in the ventral mesencephalon projecting to the basal ganglia have different sprouting capacities when stimulated by the trophic effect of a fetal striatal graft. Lateral ganglionic eminence was implanted into the lateral ventricle, the midportion of dorsal striatum, globus pallidus, or ventral striatum. Solid tissue pieces from 13- to 15-mm fetuses were stereotactically implanted into adult female Sprague-Dawley rats. At postgrafting week 4 the animals were perfused and processed for tyrosine hydroxylase (TH) immunohistochemistry. Transplants placed in the lateral ventricle were TH-negative, except for two cases with TH-positive fibers where the ependymal layer was disrupted, thereby allowing direct contact between the graft and the adjacent host striatum. The transplants placed into dorsal striatum were innervated by small patches of dopaminergic nerve fibers. Areas between the TH-positive patchy structures remained TH-negative. In grafts placed into globus pallidus, both patchy structures and a less dense TH-positive nerve fiber network was noted. The TH-positive growth pattern in transplants placed in ventral striatum was also devided into patchy and widespread growth. Grafts placed in globus pallidus and ventral striatum revealed significantly larger areas of TH-positive innervation compared with that measured in grafts placed in dorsal striatum and the lateral ventricle. In conclusion, it is possible to induce sprouting of TH-immunoreactive nerve fibers from all areas examined. The most potent areas to initiate dopaminergic growth were the globus pallidus and ventral striatum, where both a patchy dense and a widespread, less dense growth was induced. Thus, if using a trophic stimulus to induce sprouting from remaining dopaminergic nerve fibers in Parkinson’s disease, the preferential target to induce sprouting would be ventromedial striatum and growth would be guided toward dorsal striatum owing to the enhanced dopaminergic growth properties in the ventromedial areas.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 113 (1997), S. 138-143 
    ISSN: 1432-1106
    Keywords: Parkinson’s disease ; Neural transplantation ; Cell death ; Lazaroid ; Dopamine ; Free radicals ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We explored the effects of congeners of nitrogen monoxide (NO) on cultured mesencephalic neurons. Sodium nitroprusside (SNP) was used as a donor of NO, the congeners of which have been found to exert either neurotoxic or neuroprotive effects depending on the surrounding redox milieu. In contrast to a previous report that suggests that the nitrosonium ion (NO+) is neuroprotective to cultured cortical neurons, we found that the nitrosonium ion reduces the survival of cultured dopamine neurons to 32% of control. There was a trend for further impairment of dopamine neuron survival, to only 7% of untreated control, when the cultures were treated with SNP plus ascorbate, i.e. when the nitric oxide radical (NO) had presumably been formed. We also evaluated the effects of an inhibitor of lipid peroxidation, the lazaroid U-83836E, against SNP toxicity. U-83836E exerted marked neuroprotective effects in both insult models. More than twice as many dopamine neurons (75% of control) survival when the lazaroid was added to SNP-treated cultures and the survival was increased eight-fold (to 55% of control) when U-83836E was added to cultures treated with SNP plus ascorbate. We conclude that the congeners of NO released by SNP are toxic to mesencephalic neurons in vitro and that the lazaroid U-83836E significantly increases the survival of dopamine neurons in situations where congeners of NO are generated.
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  • 17
    ISSN: 1432-1106
    Keywords: Antidiuretic hormone ; Osmotic stimulus ; Anteroventral third ventricular region ; Prostaglandins ; Meclofenamate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study explored the roles of prostaglandins in the anteroventral third ventricular region, a cerebral osmoreceptor site, in the osmoregulation mechanism of vasopressin release. We injected (1 μl) prostaglandin E2 (12.8 nmol) or meclofenamate (78.3 nmol), an inhibitor of prostaglandin biosynthesis, into the brain region or the lateral cerebral ventricle of conscious rats, examining their effects on plasma vasopressin and its controlling factors in the presence or absence of an osmotic stimulus. The injection of prostaglandin E2 into the anteroventral third ventricular region augmented plasma vasopressin and arterial pressure after 5 min and 15 min, without influencing plasma osmolality, sodium, potassium, or chloride. In contrast, intraventricular injection of prostaglandin E2 did not cause any significant effect on those variables. The i.v. infusion (0.1 ml·kg−1·min−1) of hypertonic saline (2.5 mol/l) enhanced plasma vasopressin after 15 min and 30 min; this was accompanied by increased plasma osmolality, sodium, and chloride, and by unaltered or elevated arterial pressure. Meclofenamate given into the anteroventral third ventricular region 30 min before starting the hypertonic saline infusion abolished the osmotic vasopressin response without significantly changing the responses of the other variables. Histological analysis showed that the injection sites of meclofenamate in these rats were close to those of prostaglandin E2 in the anteroventral third ventricular region and included the organum vasculosum of the lamina terminalis and the surrounding area, the medial preoptic area, and periventricular and median preoptic nuclei. When injection cannulae for meclofenamate deviated from those areas incidentally or when the drug was expressly administered into the cerebral ventricle, the osmotic vasopressin response was not inhibited. Plasma vasopressin and the other variables observed during the i.v. infusion of isotonic saline (0.15 mol/l) were not affected significantly by meclofenamate administration into the anteroventral third ventricular region or the cerebral ventricle. On the basis of these results, we concluded that prostaglandins synthesized in and/or near the anteroventral third ventricular region might contribute to the facilitation of vasopressin release in the hyperosmotic state.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 113 (1997), S. 303-310 
    ISSN: 1432-1106
    Keywords: Hippocampus ; Adenosine A1 receptor ; DPCPX ; Purines ; Membrane partitioning ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Despite its potent proconvulsant effects in vitro, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) does not induce seizures when administered in vivo. This contrasts with the effects of less selective adenosine antagonists such as theophylline or cyclopentlytheophylline, and led us to reexamine the nature of DPCPX-induced epileptiform activity. In the present study, we report that proconvulsant effects of bath-applied DPCPX in rat hippocampal slices are only observed after a preceding stimulus such as NMDA receptor activation or brief tetanic stimulation. While this may be due to the absence of a basal “purinergic tone”, the relatively high interstitial concentrations of adenosine present in the slice suggest that access of the drug to A1 receptors may instead be prevented by tightly coupled endogenous adenosine, with the ternary adenosine-A1 receptor-G protein complex stabilised in the high-affinity conformation by a coupling cofactor. This implies that a substantial percentage of adenosine A1 receptors are inactive under physiological conditions, but that access of adenosine A1 receptor antagonists may be facilitated under pathological conditions. Once induced, DPCPX-evoked spiking persists for long periods of time. A “kindling” effect of A1 receptor blockade is unlikely, since persistent spiking is not usually observed with less selective A1 antagonists even after prolonged application. Alternatively, endogenous adenosine released during increased neuronal activity may activate A2 receptors during selective A1 blockade. The most important factor determining the duration of DPCPX-induced spiking, however, may be a persistence of the drug in the tissue and subsequent access to the A1 receptor via a membrane-delineated pathway, since DPCPX-induced spiking could be shown to decrease markedly after a transient superfusion of theophylline. This hypothesis, which implies that the apparent affinity of adenosine antagonists for the A1 receptor is in part a function of their membrane partitioning coefficient, is supported by a close correlation between alkylxanthine logP values obtained from the literature and theirK i value at A1 receptors, but not at the enzyme phosphodiesterase, whose xanthine binding site is presented to the cytosol. The implications for the therapeutic value of purinergic drugs are discussed.
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  • 19
    ISSN: 1432-1106
    Keywords: GABA ; Double immunostaining ; Retrograde tracing ; Diagonal band ; Disinhibition ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the septal complex, both parvalbumin and calbindin neurons cocontain GABA. In the same area, a large number of GABA-GABA synaptic connections can be observed. In order to further characterize their neurochemical nature, as well as the extrinsic and/or intrinsic origin of these GABA terminals, the following experiments were performed: (1) correlated light- and electronmicroscopic double immunostaining for calbindin and parvalbumin on septal sections of control rats; (2) light microscopic parvalbumin immunostaining of septal sections after surgical isolation (5 days) of the septum from its telencephalic or (3) hypothalamic afferents; and (4) parvalbumin immunostaining of sections prepared from the entire brain 2 days following horseradish peroxidase injection into the border between the lateral and medial septum. The results demonstrated that: (1) in a well-circumscribed, vertically longitudinal area located between the lateral and medial septum, 0.1–0.6 mm anterior to the bregma, a group of calbindin-containing, nonsomatospiny neurons are surrounded by parvalbumin-immunoreactive baskets; (2) these basket-forming axon terminals establish symmetric synaptic contacts with their targets; and (3) their cells of origin are not in the medial septum, but in the angular porition of the vertical limb. These observations indicate that a portion of the septal complex GABA-GABA synaptic connections represent functional interaction between two different types of GABAergic neurons. The presynaptic GABAergic neurons contain parvalbumin, and the postsynaptic GABAergic cells are immunoreactive for calbindin. Furthermore, a population of the medial septum/diagonal band parvalbumin neurons promect only to the hippocampus, while others, which may also send axons to the hippocampus, terminate on lateral septum calbindin cells as well.
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  • 20
    ISSN: 1432-1106
    Keywords: Urinary bladder ; Inflammation ; Mesodiencephalon ; Immunocytochemistry ; Rest-active cycle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The evoked expression of the immediate-early gene-encoded proteins c-Fos and Krox-24 was used to study activation of mesodiencephalic structures as a function of the development of cyclophosphamide (CP) cystitis in behaving rats. This article is the third of a series and completes previously published data obtained at both spinal and hindbrain levels. CP-injected animals received a single dose of 100 mg/kg i.p under transient volatile anesthesia and survived for 1–4 h in order to cover the entire postinjection period during which the disease develops. Survival times longer than 4 h were not used owing to ethical considerations. Results from CP-injected groups are compared with those from either noninjected controls or saline-injected, animals having survived for the same times as CP-injected ones. Quantitative results come from c-fos expression. At mesodiencephalic levels a high and widespread basal c-fos expression was observed in control animals; maximum staining was observed at the midthalamic level. Four groups of nuclei were identified with regard to the density of staning. The first group included nuclei showing clustered, intensely labeled cells; these areas were restricted in extent and related to the maintenance of circadian rythms (intergeniculate leaf, suprachiasmatic nucleus, dorsal parts of either paraventricular thalamic nuclei or central gray), sleep-arousal cycle (supramamillary nucleus), or changes in arterial pressure (laterodorsal tegmental nucleus). The second group included nuclei showing scattered, moderately labeled cells; these areas were widespread at all rostrocaudal levels and related to either autonomic/neuroendocrine regulations (central gray, lateral and the caudal part of the bulbar reticular formation. In contrast, more rostral subtelencephalic levels contain a variety of areas, in which maximal reaction precedes the complete development of cystitis and appears to be more involved in vegetative functions.
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  • 21
    ISSN: 1432-1106
    Keywords: Somatostatin ; Hypothalamus ; Dexamethasone ; Picrotoxin ; Push-pull perfusion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously reported the rapid response of hypothalamic somatostatin (SS) neurons to acute stress. Since it is well known that glucocorticoids (GC) are involved in neuroendocrinal stress regulation, we investigate in this study the effects of acute administration of dexamethasone (Dex) on both in vivo and in vitro SS release. Freely moving animals received stereotaxic implant of a push-pull cannula into the median eminence for 10 days, and then they were perfused with artificial cerebrospinal fluid for 120–150 min. An i.p. injection of Dex (200 or 300 μg/100 g) induced, 15–30 min later, a mean increase in SS hypothalamic output of 62.6±6.2% of basal secretion. By contrast, after 15 min incubation of hypothalamic fragments with either 10−7 or 10−6 M Dex, SS release decreased abruptly to 57.3±3.3% (n=16;P〈0.001 compared with basal release) and 78.0±9.5% (n=13;P〈0.05 compared with basal release) of basal release, respectively. Other Dex concentrations induced no variations, giving the dose-effect curve an abrupt “on-off” effect. The inhibitory effect was blocked by picrotoxin (10−4 M) and was immediately reversed when Dex was removed from the medium. Specificity was tested by using another steroid, estradiol, and another tissue, cortex. The rapid action of GC whatever the model used and in particular the blocking in vitro effect of picrotoxin could suggest that GCs act at the level of the membrane and could operate physiologically in response to stress. In addition, the opposite in vivo and in vitro effects on SS release would indicate that GCs exert two different controls on SS neurons.
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  • 22
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 113 (1997), S. 484-496 
    ISSN: 1432-1106
    Keywords: Key words Glutamate ; Muscarinic receptor ; NMDA ; Guanosine-5′-O-(2-thiodiphosphate) thrilithium salt ; Response enhancement ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study examines the ability of muscarinic receptor activation to modulate glutamatergic responses in the in vitro rat auditory cortex. Whole-cell patch-clamp recordings were obtained from layer II-III pyramidal neurons and responses elicited by either stimulation of deep gray matter or iontophoretic application of glutamate receptor agonists. Iontophoresis of the muscarinic agonist acetyl-β-methylcholine (MCh) produced an atropine-sensitive reduction in the amplitude of glutamate-induced membrane depolarizations that was followed by a long-lasting (at least 20 min) response enhancement. Glutamate depolarizations were enhanced by MCh when elicited in the presence of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/ kainate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or 2,3-diyhdroxy-6-nitro-7-sulfamoyl, benzo(F)quinoxaline (NBQX) but not the NMDA antagonists d-2-amino-5-phosphonovaleric acid (APV) or MK-801 hydrogen maleate. The magnitude of enhancement was voltage-dependent with the percentage increase greater at more depolarized membrane potentials. An involvement of NMDA receptors in these MCh-mediated effects was tested by using AMPA/kainate receptor antagonists to isolate the NMDA-mediated slow excitatory postsynaptic potential (EPSP) from other synaptic potentials. The slow EPSP and iontophoretic responses to NMDA were similarly modified by MCh, i.e., both being reduced during and enhanced (15–55 min) following MCh application. Cholinergic modulation of NMDA responses involves the engagement of G proteins, as enhancement was prevented by intracellular infusion with the nonhydrolyzable GDP analog guanosine-5′-O-(2-thiodiphosphate) trilithium salt (GDPβS). GDPβS was without effect on the early MCh-induced response suppression. Our results suggest that acetylcholine, acting at muscarinic receptors, produces a long-lasting enhancement of NMDA-mediated neurotansmisson in auditory cortex, and that this modulatory effect is dependent upon a G protein-mediated event.
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  • 23
    ISSN: 1432-1106
    Keywords: Key words Forebrain ischemia ; Hyperglycemia ; Hippocampus ; Bioenergetic state ; Cyclosporin A ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A recent study from this laboratory has shown that brief transient ischemia (2 min 30 s) in normo- and hyperglycemic rats leads to moderate neuronal necrosis in CA1 cells of the hippocampus, of equal density in the two groups. However, hyperglycemic animals failed to depolarize during the ischemia, nor did they show a decrease in extracellular calcium concentration. The present study was undertaken to study the metabolic correlates to these unexpected findings. Normoglycemic (plasma glucose ∼6 mM) and hyperglycemic (∼20 mM) rats were subjected to ischemic periods of 1 min and 2 min 15 s (2 min 30 s with freezing delay considered), and their brains were frozen in situ. Samples of dorsal hippocampus were dissected at –22°C and extracted for the measurement of phosphocreatine (PCr), creatine, ATP, ADP, AMP, glucose, glycogen, and lactate. Normoglycemic animals showed rapid depletion of PCr, ATP, glucose, and glycogen, and a rise in lactate content to 10–12 mM·kg–1 during the ischemia. Hyperglycemic animals displayed a more moderate rate of fall of PCr and ATP, with ATP values exceeding 50% of control after 2 min 30 s. Glycogen stores were largely maintained, but degradation of glucose somewhat enhanced the lactic acidosis. The results demonstrate that hyperglycemic rats maintained ATP at levels sufficient to prevent cell depolarization and calcium influx during the ischemic period. However, the metabolic perturbation observed must have been responsible for the delayed neuronal damage. We speculate that lowered ATP, increased inorganic P, and oxidative stress triggered a delayed mitochondrial permeability transition (MPT), which led to delayed neuronal necrosis. This assumption was supported by a second series of experiments in which CA1 damage in hyperglycemic rats was prevented by cyclosporin A, a virtually specific inhibitor of the MPT.
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  • 24
    ISSN: 1432-1106
    Keywords: Key words Synapse ; Axo-axonic synaptic contacts ; Trigeminal motor nucleus ; Immunogold ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Electron-microscopic immunolabelling methods were used to study the relationships between glutamate-immunoreactive and γ-aminobutyric acid (GABA)-immunoreactive synapses on trigeminal motoneurones labelled by the retrograde transport of horseradish peroxidase. Serial sections were cut through the motor nucleus, alternate sections were incubated with antibodies to glutamate and GABA, and the immunopositive nerve terminal profiles were recognized using a quantitative, postembedding immunogold method. Boutons exhibiting high levels of glutamate immunoreactivity and GABA-immunoreactive boutons both formed axo-dendritic and axo-somatic synaptic contacts on labelled motoneurones. Boutons strongly immunopositive for glutamate were not immunopositive for GABA, and vice versa. Strongly glutamate immunoreactive boutons received axo-axonic synaptic contacts but did not form such contacts, while GABA-immunoreactive boutons formed axo-axonic synapses but did not receive them. The presynaptic elements at all axo-axonic synapses on to glutamate-immunoreactive boutons sampled were GABA-immunopositive. These data provide ultrastructural evidence in support of the roles of glutamate and GABA as transmitters at synapses on trigeminal motoneurones, and for presynaptic control of transmission at glutamatergic synapses by GABA acting at receptors at axo-axonic synapses. The vast majority (more than 90%) of strongly glutamate immunoreactive boutons contained spherical synaptic vesicles, in contrast to GABA-immunoreactive boutons, which contained pleomorphic vesicles. Most of the glutamate-immunoreactive boutons (67%) formed asymmetrical synaptic active zones, many of which (47% of total) were associated with subsynaptic dense ”Taxi” bodies (T-terminals), while a smaller population of boutons (21%) formed symmetrical synapses, and a few (11%) made synapses associated with subsynaptic cisternae (C-terminals). The heterogeneity of active zone ultrastructure of boutons identified as being glutamatergic on the basis of their high levels of immunolabelling is discussed in relation to possible differences in co-transmitters released, origins of the synaptic input or post-synaptic receptor subtypes activated.
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  • 25
    ISSN: 1432-1106
    Keywords: Key words Substantia nigra ; Superior colliculus ; Parvicellular reticular formation ; Orofacial movement ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We examined a nigro-tecto-bulbar pathway to the parvicellular reticular formation (RFp), where many premotor neurons for orofacial motor nuclei are known to be distributed, by using a combined anterograde and retrograde tracing method. After contralateral injections of biotinylated dextranamine (BDA) into the dorsolateral part of the substantia nigra (SNr) and cholera toxin B subunit (CTb) into the RFp, overlapping distributions of BDA-labeled terminals and CTb-labeled neuronal cell bodies were found in the lateralmost part of the superior colliculus (SC) ipsilateral or contralateral to the site of BDA injection or CTb injection, respectively. After contralateral injections of BDA into the SNr and horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) injection into the RFp, ipsilateral labeled axon terminals with BDA were found to make symmetrical synaptic contacts with the somata and dendrites of contralateral labeled neurons with WGA-HRP in the lateralmost part of the SC. Furthermore, we demonstrated that BDA-labeled axon terminals were immunoreactive for GABA, by using the anterograde tracing method combined with immunohistochemistry for GABA. Thus, GABA-like immunoreactive fibers originating from the dorsolateral part of the SNr make monosynaptic contacts with the tectal neurons sending their axons to the RFp.
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  • 26
    ISSN: 1432-1106
    Keywords: Key words Nerve growth factor ; Brain-derived neurotrophic factor ; Locomotion ; Nicotinic receptor ; Intracerebroventricular administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The acute and subacute effects of intracerebroventricularly (ICV) administered nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) on locomotor activity were evaluated in awake adult rats. Immediately after ICV injection through an implanted cannula, locomotor activity was measured by a computerized system using infrared photocells, which allowed us to record locomotion, motility, and rearing simultaneously. A single dose of 5 μg mouse β-NGF produced significant increases in horizontal ambulatory components of locomotor activity (locomotion and motility), but not vertical movement (rearing) 30–45 min after ICV administration. These increases lasted for at least 3–4 h. Systemic injection of 2.0 mg/kg mecamylamine, a central nicotinic receptor antagonist, inhibited the hyperactivity induced by NGF. Systemic injection of 0.5 mg/kg scopolamine, a muscarinic receptor antagonist, did not interfere with the NGF effects. Thus, while scopolamine induced marked increases in all three measures of behavior in both NGF and cytochrome-c-treated animals, locomotion and motility remained significantly higher in the NGF group. Immunohistochemistry demonstrated that NGF diffused readily from the ventricular space into brain parenchyma on the injected side and could be visualized 1 h after ICV injection. These results suggest that ICV administration of NGF increases locomotor activity by inducing acetylcholine release, and that nicotinic receptors are involved in the hyperactivity induced by NGF. ICV administration of 5 μg recombinant human BDNF had no significant effect on locomotor activity during the 0- to 4-h period after ICV injection. However, it produced significant decreases in locomotion, motility, and rearing 24–26 h later. Hence ICV administration of BDNF has entirely different effects on animal behavior from those evoked by NGF. While NGF elicits increases in ambulatory behavior within hours, BDNF causes delayed decreases in ambulatory behavior.
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  • 27
    ISSN: 1432-1106
    Keywords: Key words Dihydrokainate ; Kainate ; Hippocampal cell death ; MAP2 immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Neurotoxicity mediated by glutamate is thought to play a role in neurodegenerative disorders, and alterations in cytoskeletal proteins are possibly involved in the mechanisms of neuronal death occurring in Alzheimer’s disease. In the present work we studied the neurotoxic effects of the intrahippocampal injections of the glutamate transport inhibitor dihydrokainate as compared to those of kainate, as well as the concomitant changes in the microtubule-associated protein MAP2. Neuronal alterations were assessed at 3, 12, 24, and 48 h by Nissl staining and immunocytochemistry of MAP2. At 3 h, both compounds induced neuronal damage that was correlated with loss of dendritic MAP2 immunoreactivity. Neuronal damage was more evident at 12 h and 24 h after drug injection, and at these times an accumulation of MAP2 in the somata of pyramidal neurons was observed. The effects of dihydrokainate were restricted to the CA1 region and totally prevented by the N-methyl-d-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), but not by the non-NMDA receptor antagonist 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline (NBQX). In contrast, kainate-induced alterations included CA1, CA3, and CA4 subfields, and the changes in CA1 were prevented by NBQX, while MK-801 was ineffective. These results suggest that early MAP2 disruption may be a marker of the excitotoxicity due to activation of different glutamate receptors located in discrete hippocampal regions.
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  • 28
    ISSN: 1432-1106
    Keywords: Key words “Central pain” ; Picrotoxin ; Epilepsy ; Acetylcholine ; Cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In this study, we examined the modulation by acetylcholine of electrocorticographical (ECoG) ictal events and spontaneous pain-like behaviors following cortical application of the GABAA antagonist picrotoxin in the awake rat. Distilled water as vehicle, the cholinomimetic substance eserine, and the general muscarinic antagonist atropine were microinjected 10 min before the second microinjection of 2 μg picrotoxin into the hind paw region of the somatomotor cortex (SmI). Under these conditions, we observed that eserine (physostigmine, 1 μg, 10 μg, and 20 μg) did not consistently modify the number of the picrotoxin-induced ECoG spikes and bursts, but instead produced a massive enhancement of the number of hind paw licks compared with vehicle at 10 μg and, to a lesser extent, the number of the stereotyped “turn-in” and “neglected” paws following picrotoxin. In contrast, atropine (l μg, 10 μg, and 20 μg) increased the number of the picrotoxin-induced spikes and bursts at 10 μg and, at all doses, decreased the number of the picrotoxin-induced pain-like symptoms. Statistically significant changes for the number of paw lifts, licks, and “turn-in” paws were observed only with 10 μg. These results tend to show that epilepsy and pain are not strictly related to each other and also emphasize the cortex as a target for interactions between GABA and acetylcholine relative to “central” pain.
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  • 29
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    Experimental brain research 114 (1997), S. 590-594 
    ISSN: 1432-1106
    Keywords: Key words Calcium ; Intracellular recording ; Desensitization ; Brain slice ; 5-Amino-phosphonovaleric acid ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The influence of age on NMDA receptor-mediated excitatory postsynaptic potentials (EPSPs) was characterized in striatal in vitro brain slices using intracellular recording techniques. All slices were bathed in bicuculline methiodide (20 μM) to isolate EPSPs from intrinsic inhibition and Mg2+ was omitted from the artificial cerebral spinal fluid to reduce voltage-dependent fluctuations of NMDA receptor-mediated EPSPs. The NMDA receptor-mediated component of the EPSP was determined by comparing EPSP areas before and after block of NMDA receptors with 5-amino-phosphonovaleric acid (AP-5; 30 μM). No age difference was found in the percentage contribution of the NMDA receptor-mediated component of the EPSP, but an age difference was observed in the response to removal of AP-5. On average, washout of AP-5 produced a significant enhancement of the EPSP in young cells, while in aged cells the EPSP returned, on average, to the pre-AP-5 control level. These data demonstrate that NMDA receptors contribute equally to EPSPs at young and aged synapses and that age-related decreases in the number of NMDA receptors may be related to synapse loss. In addition, the response to removal of AP-5 suggests that functional properties of NMDA receptors may also be altered by aging.
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  • 30
    ISSN: 1432-1106
    Keywords: Key words Excitatory amino acids ; Calcium-binding proteins ; Thalamic nuclei ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Topographical and quantitative features of medial thalamic neurons in which aspartate (ASP) or glutamate (GLU) might act as neurotransmitters were investigated in the rat. The calcium-binding protein calbindin D-28k (CB) was exploited as a marker of neuronal subsets, thus allowing us to study also the relationships between the CB-containing neurons and those immunoreactive to excitatory amino acids. Double immunocytochemistry of ASP and CB or GLU and CB was performed in 40-μm-thick sections. The three markers were distributed in the thalamic midline, mediodorsal, anterior intralaminar and ventromedial nuclei, with regional variations. ASP-immunoreactive neurons appeared more numerous than the GLU-immunoreactive ones throughout these structures; ASP-CB or GLU-CB double-immunostained neurons were evident. ASP-, GLU- and CB-immunoreactive cells were then quantitatively evaluated in 5-μm-thick consecutive sections. Interindividual variations and different anti-ASP and anti-GLU antibodies did not result in significant differences. ASP and GLU were not co-localized. Single ASP- or GLU-immunoreactive neurons accounted for 60% of the total number of immunostained cells, and single ASP-immunopositive cells represented more than half of these neurons. Among the CB-immunoreactive cells (40% of the total), half were double immunostained; the proportion of double CB-ASP-immunopositive neurons was sevenfold higher than that of the CB-GLU-immunoreactive ones. These results indicate that ASP may act as excitatory neurotransmitter in a relatively high proportion of medial thalamic neurons, in which ASP frequently coexists with CB. Approximately 50% of the CB-immunoreactive cells did not contain either ASP or GLU, suggesting that some medial thalamic neurons may utilize a different neurotransmitter.
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  • 31
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    Experimental brain research 116 (1997), S. 519-524 
    ISSN: 1432-1106
    Keywords: Key words Lateral hypothalamus ; Ventromedial hypothalamus ; Interferon ; Glucose ; Single cell ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Interferon-α (IFN) therapy induces feeding suppression that resembles anorexia. The hypothalamic glucose-sensitive neurons engage in feeding behavior. Coronal sections of rat brains, containing both the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH), as well as single-cell recordings were used to study the interaction between IFN and glucose-sensitive neurons. IFN suppressed the majority (78%) of LH neurons, while reduction in glucose concentration elicited excitation in the majority (85%) of the same neurons. The opposite effects were observed in the VMH, where IFN excited the majority of neurons (61%), and reduction in glucose concentration exerted the opposite effects in 64% of VMH recordings. Concomitant IFN and glucose reduction exhibited only the effects elicited by IFN, regardless of whether the glucose reduction caused excitation (LH) or suppression (VMH). This observation suggests that IFN causes anorexia by modulating the LH and VMH glucose-sensitive neurons.
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  • 32
    ISSN: 1432-1106
    Keywords: Hypoxia-ischaemia ; Magnetic resonance spectroscopy ; Cerebral energy metabolism ; Newborns ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determined whether focal cerebral injury caused by unilateral carotid artery occlusion and graded hypoxia in developing rats led to a delayed impairment of cerebral energy metabolism and whether the impairment was related to the magnitude of cerebral infarction. Forty-two 14-day-old Wistar rats were subjected to right carotid artery ligation, followed by 8% oxygen for 90 min. Using a 7T MRS system,31P brain spectra were collected during the period from before until 48 h after hypoxia-ischaemia. Twenty-eight control animals were studied similarly. In controls, the ratio of the concentration of phosphocreatine ([PCr]) to inorganic orthophosphate ([Pi]) was 1.75 (SD 0.34) and nucleotide triphosphate (NTP) to total exchangeable phosphate pool (EPP) was 0.20 (SD 0.04): both remained constant. In animals subjected to hypoxia-ischaemia, [PCr] to [Pi] and [NTP] to [EPP] were lower in the 0- to 3-h period immediately following the insult: 0.87 (0.48) and 0.13 (0.04), respectively. Values then returned to baseline level, but subsequently declined again: [PCr] to [Pi] at −0.02 h−1 (P〈0.0001). [PCr] to [Pi] attained a minimum of 1.00 (0.33) and [NTP] to [EPP] a minimum of 0.14 (0.05) at 30–40 h. Both ratios returned towards baseline between 40 and 48 h. The late declines in high-energy phosphates were not associated with a fall in pHi. There was a significant relation between the extent of the delayed impairment of energy metabolism and the magnitude of the cerebral infarction (P〈0.001). Transient focal hypoxia-ischaemia in the 14-day-old rat thus leads to a biphasic disruption of cerebral energy metabolism, with a period of recovery after the insult being followed by a secondary impaiment some hours later.
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  • 33
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    Experimental brain research 113 (1997), S. 520-533 
    ISSN: 1432-1106
    Keywords: Key words Spinal Ia terminations ; Action potentials ; Baclofen ; Calcium influx ; Cat ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In the ventral horn of the lumbar spinal cord of cats anaesthetised with pentobarbitone sodium, microelectrophoretically administered (–)-baclofen, but not (+)-baclofen, reversibly reduced the duration of the orthodromic action potential of muscle group Ia afferent terminations, but not those of muscle group I afferent myelinated fibres. The presumably submicromolar concentrations are already known to reversibly reduce excitatory transmitter release from muscle group Ia afferent terminations. Action potential durations were estimated from threshold recovery curves after an orthodromic impulse using an extracellular microstimulation technique. Both of these presynaptic effects of (–)-baclofen were blocked by baclofen antagonists, and neither appeared to be reduced by the potassium channel blocking agents tetraethylammonium and 4-aminopyridine. Tetraethylammonium and 4-aminopyridine also did not significantly modify the reduction by (–)-baclofen of monosynaptic field potentials in the lumbar cord of rats anaesthetised with pentobarbitone sodium. In the cat the maximum reduction by (–)-baclofen of termination action potentials was considerably less than that produced by cadmium ions, which, unlike (–)-baclofen, also reduced the action potential duration of group I myelinated fibres. These findings are consistent with a reduction by (–)-baclofen of the influx of calcium through voltage-activated channels in the membrane of group Ia terminations, a proposal which also accounts for the reduction by (–)-baclofen of the release of GABA at axo-axonic depolarizing synapses on these terminations. The results are discussed in relation to the mode of action of (–)-baclofen and the different sensitivities of transmitter release at various central synapses.
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  • 34
    ISSN: 1432-1106
    Keywords: Key words Species differences ; CA2 ; Retrograde tracing ; Colocalization ; Theta rhythm ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Our recent studies showed the co-existence of substance P and calretinin in the supramammillo-hippocampal pathway of monkeys, as well as species differences in the synaptic targets of extrinsic substance P fibers in the hippocampi of monkeys and rats. Experiments used: (1) single and multiple stereotaxic injection of wheat germ agglutinin-conjugated HRP into the hippocampus and immunostaining for substance P in the supramammillary area; (2) colocalization of substance P and calretinin in supramammillary area cells; and (3) colocalization of these two neurochemicals in retrogradely labeled supramammillary projective cells of both male and female rats. These demonstrated: (a) many calretinin- and fewer substance P-immunoreactive neurons retrogradely labeled in the ipsilateral supramammillary area; (b) approximately 74% of all substance P cells contain calretinin and 9% of the calretinin neurons co-contain substance P; and, most importantly (c) none of the retrogradely labeled supramammillary cells colocalize calretinin and substance P. These results indicate the presence of two distinct supramammillo-hippocampal projections in the rat, one that contains substance P and the other calretinin. The latter innervates the same areas as those in the monkey, and the former terminates only in the CA2 hippocampal subfield.
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  • 35
    ISSN: 1432-1106
    Keywords: Key words Hippocampus ; Learning ; Memory ; Recovery ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The monosialoganglioside GM1 is a compound with neurotrophic properties found to foster functional recovery in various paradigms of brain damage. The present experiment examined whether systemic treatment with GM1 may facilitate behavioral recovery in rats with fimbria-fornix lesions and intrahippocampal grafts rich in cholinergic neurons. Among 68 Long-Evans female rats, 46 sustained a bilateral electrolytic lesion of the fimbria and the dorsal fornix and 22 were sham-operated. Fourteen days later, half the lesioned rats were subjected to intrahippocampal grafts of a fetal septal cell suspension. Starting a few hours after lesion surgery and over a 2-month period, half the rats of each surgical treatment group received a daily injection of GM1 (30 mg/kg i.p.), the other half being injected with saline as a control. All rats were subsequently tested for locomotor activity and radial maze learning. The lesions induced locomotor hyperactivity and impaired learning performances in both an uninterrupted and an interrupted radial maze testing procedure. In all rats with surviving grafts, the grafts had provided the hippocampus with a new and dense organotypic acetylcholinesterase-positive innervation pattern which did not differ between saline- and GM1-treated subjects. The scores/performances of the rats that had received only the grafts or only the GM1 treatment did not differ significantly from those of their respective lesion-only counterparts. However, in the radial-arm maze task, the grafted rats given GM1 showed improved learning performances as compared with their saline-treated counterparts: they used more efficient visit patterns under the uninterrupted testing conditions and made fewer errors under the interrupted ones. The results suggest that GM1 treatment or intrahippocampal grafts used separately do not attenuate the lesion-induced behavioral deficits measured in this experiment. However, when GM1 treatment and grafts are used conjointly, both may interact in a manner allowing part of these deficits to be attenuated.
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  • 36
    ISSN: 1432-1106
    Keywords: Key words Anionic surfactants ; Sodium dodecyl sulphate ; Blood-brain barrier ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The blood-brain barrier (BBB) arises from epithelial-like tight junctions that virtually cement adjoining capillary endothelium together in the brain microvascolature. Several experimental manipulations have been shown able to increase the permeability of brain capillaries, by altering endothelial cell membrane integrity or activating specific biochemical pathways involved in regulation of BBB functionality. Because of its amphiphilic nature, sodium dodecyl sulphate (an anionic surfactant widely used as solubilizer or stabilizer in several pharmaceutical preparations; SDS) may enter into interactions with the major membrane components, which are lipids and proteins. The aim of the present study was to determine the effect of an intracarotid infusion of SDS (25, 50 and 100 µg/kg; infusion rate: 3 ml/min for 30 s) on the functionality of the BBB in the rat. An extensive, dose-dependent Evans blue extravasation was observed, in the ipsilateral brain hemisphere, 15 min following SDS infusion. These results were confirmed by the significant increase in [14C]α-aminoisobutyric acid ([14C]AIB) transport (evaluated by calculating a unidirectional transfer constant, K i, for the tracer from blood to brain) measured in several ipsilateral brain regions 2 min after SDS infusion; this SDS-elicited BBB opening to [14C]AIB proved to be reversible. Since the BBB is created by the plasma membrane and tight junctions of the endothelial cells, the change in BBB permeability caused by SDS might be explained as a nonspecific surfactant-membrane interaction. Furthermore, SDS might affect the functional characteristics of brain vascular endothelial cells by an interaction with specific BBB proteins and/or biochemical pathways. In conclusion, one can suggest that intracarotid infusion of SDS might provide a useful clinical approach for the intentional introduction of different substances into the brain. On the other hand, these findings should call attention to possible dangerous consequences of using SDS as solubilizer in drug excipients.
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  • 37
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    Experimental brain research 116 (1997), S. 399-405 
    ISSN: 1432-1106
    Keywords: Key words Blood-CSF barrier mitochondrial volume ; Digital electron microscopy ; Cuboidal epithelium ; Rat ; Mouse ; Rabbit ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The objective of the present study was to examine the apparent work capacity of one of the two separate membrane systems (the blood-cerebrospinal fluid barrier) that isolate the mammalian brain extracellular fluid (and cerebrospinal fluid, CSF) from plasma. Digitized analyses of electron-microscopic images provided estimates of mitochondrial volumes, which were expressed as a percentage of the cell cytoplasm. We recorded a high mitochondrial content of 12–15% in the cuboidal epithelium of primate choroid plexus, which was consistent in vervet, rhesus, and squirrel monkeys, as well as in baboons. Similarly high mitochondrial contents were observed in the rabbit, rat, and mouse choroid plexus. It has been postulated that the high mitochondrial content of brain endothelium is associated with maintaining the ionic gradients within the central nervous system. We observed that the mitochondrial content of the choroid plexus (where CSF is produced) was slightly higher than in (prior measurements of) the blood-brain barrier (BBB). In addition, surface areas at the apical borders of the choroid plexus epithelia (where the Na+K+ATPase activity has been localized) were increased 7- to 13-fold over the basal borders, in the primate species examined. The observation of high mitochondrial volumes in choroid plexus cells is consistent with the suggestion that increased mitochondrial densities seen in choroidal epithelia and BBB capillaries provide a metabolic work capability for both secretory activities and maintaining ionic gradients across blood-CSF barriers.
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  • 38
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    Experimental brain research 117 (1997), S. 324-340 
    ISSN: 1432-1106
    Keywords: Key words Trigeminal nerve ; Mechanoreceptors ; Cutaneous sensory nerve ending ; Perivascular innervation ; Vibrissae ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  It is well established that sensory perception becomes impaired with advancing age and that, in parallel, dystrophy and degeneration of axons occur in sensory pathways. In this study, the impact of aging was examined in the mystacial pad, which receives a large variety of sensory nerve endings organized in a highly predictable pattern. Mystacial pad specimens from aged (30 months old) and young adult (2–3 months old) female Sprague-Dawley rats were processed, in parallel, for immunohistochemical analyses with antibodies against human neuronal cytoplasmic protein (protein gene product 9.5), transmitter enzymes, and several neuropeptides. Several changes in cutaneous innervation including both degenerative and regenerative processes were evident in the aged rat: (1) the Merkel endings and lanceolate endings that emanate from large-caliber afferents in the whisker follicles were reduced and showed signs of degeneration. Furthermore, a reduction of piloneural complexes at the intervibrissal hairs were evident, but only in aged rats that showed more severe behavioral sensorimotor disturbances. In contrast, Ruffini endings as well as mechanoreceptors emanating from medium-caliber axons, i.e., transverse lanceolate and reticular endings, appeared normal. (2) A reduction was evident among two sets of unmyelinated epidermal endings; however, the epidermal innervation affiliated with the intervibrissal hairs appeared normal in the aged rat. (3) A loss of sympathetic neuropeptide tyrosine (NPY) or tyrosine hydroxylase-immunoreactive (IR) and somatosensory Calcitonin gene-related peptide (CGRP)-IR perivascular axons was paralleled by an increase in presumed parasympathetic NPY/CGRP-IR axons. (4) Two “novel” networks of fine-caliber axons were observed in the outer and inner root sheaths of the whisker follicles in the aged rat. (5) NPY was present in a population of small-caliber, somatosensory CGRP-IR axons in the aged rat. This may represent a de novo synthesis, since, normally, NPY-like immunoreactivity is not observed in this set of axons. Our results suggest that the sensory impairments occurring with advancing age are part of a peripheral process instigated by changes in nerve-target interactions and/or incapacitation of the neuronal machinery to sustain the axonal integrity.
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  • 39
    ISSN: 1432-1106
    Keywords: Key words Locomotor recovery ; Neural transplantation ; Fictive locomotion ; Serotonin ; 6-Hydroxydopamine ; Zimelidine ; Rat ; Spinal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Locomotor movements are programmed in a specialised neuronal network that is localised in the central nervous system and referred to as the central pattern generator (CPG) for locomotion. This CPG can be activated by pharmacological agents such as monoamines. The aim of the present study was to try to activate the CPGs by using cells that are supposed to release serotonin locally. Adult chronic spinal rats were injected with embryonic brainstem neurons within the spinal cord under a thoracic transection. This procedure resulted in a monoaminergic reinnervation of the lumbar enlargement. With the help of a specific neurotoxin for noradrenergic neurons (6-hydroxydopamine), it was possible to isolate the serotonergic system. After such transplantation of monoaminergic neurons and even with serotonergic neurons alone, a bilateral, alternating, rhythmic locomotor-like activity recovered in hindlimbs. Furthermore, this locomotor-like activity was clearly facilitated when the re-uptake of serotonin was blocked by zimelidine. Therefore, we conclude that transplanted embryonic serotonergic neurons are able to activate the CPG for locomotion.
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  • 40
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    Experimental brain research 114 (1997), S. 51-62 
    ISSN: 1432-1106
    Keywords: Key words Pupillary light reflex ; Pretectum ; Anterograde and retrograde tracing ; GABA immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The olivary pretectal nucleus is a primary visual centre, involved in the pupillary light reflex. In the present study an ultrastructural analysis was made of the olivary pretectal nucleus by means of separate, anterograde and retrograde tracing techniques and immunohistochemistry of gamma-aminobutyric acid. Large-projection neurons and two types of gamma-aminobutyric acid-immunoreactive (GABA-ir) neurons are observed in the olivary pretectal nucleus. The primary dendrites of the projection neurons have a dichotomous appearance, the secondary dendrites a multipolar appearance. At the ultrastructural level the projection neurons have well-developed Golgi fields, abundant rough endoplasmic reticulum and the nucleus is always heavily indented. Numerous small GABA-ir neurons and a few medium-sized GABA-ir neurons are found. The small GABA-ir neurons contain a few stacks of rough endoplasmic reticulum and the nucleus is oval-shaped. The medium-sized GABA-ir neurons have well-developed Golgi fields, a moderate number of rough endoplasmic reticulum stacks and an indented nucleus. GABA-positive dendritic profiles containing vesicles also are observed. In the neuropil of the olivary pretectal nucleus, retinal terminals are found that contain round clear vesicles and electron-lucent mitochondria. They make asymmetric synaptic contacts (Gray type I) with dendritic profiles and with profiles containing vesicles. Terminals originating from the contralateral olivary pretectal nucleus exhibit small, round clear vesicles, electron-dense mitochondria and make asymmetric synaptic contacts (Gray type I) mainly with dendritic profiles. Two types of GABA-ir terminals were found. One type is incorporated in glomerulus-like arrangements, whereas the other type is not. GABA-ir terminals contain pleomorphic vesicles, electron-dense mitochondria and make symmetric synaptic contacts (Gray type II). Retinal terminals, terminals originating from the contralateral olivary pretectal nucleus and GABA-ir terminals are organized in glomerulus-like structures, in which dendrites of the large projection neurons form the central elements. Triadic arrangements are observed in these structures; a retinal terminal contacts a dendrite and a GABA-ir terminal and the GABA-ir terminal also contacts the dendrite. The complexity of the synaptic organization and the abundancy of inhibitory elements in the olivary pretectal nucleus suggest that the olivary pretectal nucleus is strongly involved in processing visual information in the pupillary light reflex arc.
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  • 41
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    Experimental brain research 114 (1997), S. 143-148 
    ISSN: 1432-1106
    Keywords: Key words γ-Aminobutyric acid ; Muscimol ; Baclofen ; d.c. potential ; Extracellular pH ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Generally, increases in cortical activity go in parallel with negative shifts and decreases with positive shifts of cortical d.c. potentials. The aim of the present investigation was to test the effects of the inhibitory transmitter γ-aminobutyric acid (GABA) and of GABA receptor agonists on cortical d.c. potentials. Concomitant changes of local pH were measured to get first insights as to the mechanisms of the evoked d.c. changes. The experiments were carried out on anesthetized and artificially ventilated rats. d.c. potentials were recorded at a cortical depth of about 1000 μm by glass microelectrodes. Extracellular pH was measured by ion-selective microelectrodes. GABA (0.1 mol/l), the GABAA receptor agonist muscimol (0.1 mmol/l) and the GABAB receptor agonist baclofen (0.1 mmol/l) were microejected by pressure pulses at a distance of 20–40 μm from the recording electrode. GABA evoked positive d.c. shifts with low pressure ejection and long application times. With increasing pressure the positive d.c. shifts were initially superimposed by negative ones. The GABAA receptor agonist muscimol elicited negative and the GABAB receptor agonist baclofen positive displacements of the d.c. potential independent of application time or pressure. The negative d.c. shifts induced by GABA and muscimol were associated with an extracellular alkalization of up to 0.1 pH units. The findings led one to assume (1) that the negative d.c. shift after GABA application was due to a neuronal depolarization and to an increase in excitation via local alkalization and (2) that the positive d.c. shift mirrored neuronal hyperpolarization.
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  • 42
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    Experimental brain research 116 (1997), S. 186-190 
    ISSN: 1432-1106
    Keywords: Key words Pilocarpine ; NPY ; Hippocampus ; Epilepsy ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Neuropeptide-Y (NPY) is expressed by granule cells and mossy fibres of the hippocampal dentate gyrus during experimental temporal lobe epilepsy (TLE). This expression may represent an endogenous damping mechanism since NPY has been shown to block seizure-like events following high-frequency stimulation in hippocampal slices. The pilocarpine (PILO) model of epilepsy is characterized by an acute period of status epilepticus followed by spontaneous recurrent seizures and related brain damage. We report peroxidase-antiperoxidase immunostaining for NPY in several brain regions in this model. PILO-injected animals exhibited NPY immunoreactivity in the region of the mossy fibre terminals, in the dentate gyrus inner molecular layer and, in a few cases, within presumed granule cells. NPY immunoreactivity was also dramatically changed in the entorhinal cortex, amygdala and sensorimotor areas. In addition, PILO injected animals exhibited a reduction in the number of NPY-immunoreactive interneurons compared with controls. The results demonstrate that changes in NPY expression, including expression in the granule cells and mossy fibres and the loss of vulnerable NPY neurons, are present in the PILO model of TLE. However, the significance of this changed synthesis of NPY remains to be determined.
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  • 43
    ISSN: 1432-1106
    Keywords: Key words Cocaine ; Dorsolateral septal nucleus ; Intracellular electrophysiology ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We investigated persistent changes in single-neuron activity in the dorsolateral septal nucleus (DLSN) induced by chronic administration of cocaine. Intracellular recording techniques were utilized with an in vitro brain slice preparation to examine the effects of in vivo chronic cocaine administration, for 7 days or 14 days, on the distribution of electrophysiologically characterized DLSN cells. We have previously distinguished DLSN neurons into three major types (I, II, and III), based upon their action potential configuration and firing pattern. This study demonstrated that type III neurons were over-represented in brain slices obtained from rats treated chronically with cocaine in vivo for 14 days when compared with brain slices obtained from rats treated either with cocaine for only 7 days or with saline and never exposed to cocaine. These data provide further evidence that neurons undergo plastic changes following chronic cocaine administration.
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  • 44
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    Experimental brain research 114 (1997), S. 454-460 
    ISSN: 1432-1106
    Keywords: Key words Glutamate receptors ; Calbindin ; Colocalization ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The lateral septum receives a massive innervation by excitatory amino acid-containing limbic cortical and hypothalamic afferents, and previous studies have described a wide distribution of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-containing neurons in this area. The aim of this study was to determine whether different subtypes of AMPA receptors are expressed in the same neurons. Furthermore, considering the fact that a population of lateral septal cells, the ”somatospiny neurons,” are GABAergic calbindin-containing cells, the coexistence of each subtype of AMPA receptor with calbindin was also investigated. Colocalization experiments were performed on adjacent vibratome sections of the lateral septal area for GluR1 and GluR2/3 AMPA-receptor subunits, GluR1 and calbindin, GluR2/3 and calbindin, as well as GluR1 plus calbindin and GluR2/3 plus calbindin, using the ”mirror” colocalization technique. The results are summarized as follows: (1) GluR1 is present in the soma and most intensively expressed in dendrites and somatic and dendritic spines; while GluR2/3 is associated with the soma and proximal dendrites of the neurons. (2) Forty-one percent of the AMPA receptor-containing neurons cocontain GluR1 and GluR2/3. (3) Thirty-eight percent of GluR1- and 28% of GluR2/3-labeled cells express calbindin. (4) Sixty-two percent of the calbindin-immunoreactive neurons contain GluR1 and 51% of them express GluR2/3. (5) Half of the neurons expressing both GluR1 and GluR2/3 also contain calbindin. (6) The distribution of GluR1 plus GluR2/3-containing, GluR1 plus calbindin-containing, and GluR2/3 plus calbindin-containing neurons in the lateral septum are homogeneous. This study indicates the existence of multiple populations of AMPA receptor- and calbindin-containing neurons in the lateral septal area.
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  • 45
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    Experimental brain research 114 (1997), S. 483-491 
    ISSN: 1432-1106
    Keywords: Key words CNS injury ; Adult ganglion cells ; Regeneration ; Visual function ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The mechanisms of neuronal network response to axotomy are poorly understood. In one of the favoured models used to study the fate of injured neurons in the adult rat visual system, appreciable numbers of retinal neurons survive optic nerve injury under conditions of microglia-targeted neuroprotection. Rescued neurons can regenerate their axons and become target-dependently stabilised after reconnection with their natural visual centres by means of a peripheral nerve graft, which, in addition to guidance, actively supports axonal growth. The mechanisms that control regenerative axonal growth and resynaptogenesis include coordinated cell-cell interactions between growing neurites and target cells in order to establish a meaningful reconnectivity. Here the function of the regenerating visual circuitry was first studied by monitoring the ability of animals to discriminate spatial patterns, and second by recording visual evoked cortical potentials (VEPs) in the same animals. These functions were correlated with neuroanatomical studies of the retinotopic organisation of regenerating axons. To achieve these goals, adult rats were behaviourally trained in a Y-maze to discriminate between vertical and horizontal stripes. Both optic nerves were transected, and the regenerating axons of one optic nerve were guided into the area of optic tract with a peripheral nerve graft according to the protocols of neuroprotection and simultaneous grafting, in order to enable large numbers of axons to reinnervate the major visual targets in the midbrain and thalamus. Postoperative testing of the animals showed a marked improvement of visual perception and behaviour. The VEPs of the same animals were measurable indicating a restoration of the visual circuitry including the ascending corticopedal connections. Neuroanatomical assessment of the fibre topography within the graft and the area of termination revealed a rough topographic organisation that may account for restoration of the function. These results suggest that interrupted central pathways can be functionally reconnected by providing a neuroprotective environment in combination with peripheral nerve grafts to by-pass lesions.
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  • 46
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    Experimental brain research 114 (1997), S. 518-524 
    ISSN: 1432-1106
    Keywords: Key words Hippcocampus ; Aconitine ; Veratridine ; Calcium ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Extracellular recording of the stimulus-evoked population spike was performed in the CA1 area of rat hippocampal slices in order to investigate delayed effects of the plant alkaloids aconitine and veratridine. Veratridine (1 µM and 10 µM) suppressed the orthodromic and antidromic population spike. After washout of the drug, only a partial recovery was obtained. Aconitine (1 µM) exerted the same inhibitory action as veratridine. However, after washout, the spike amplitude was enhanced compared with the control. This enhancement of the spike amplitude was dependent on the concentration of aconitine and was maintained during the observation period of at least 2 h. Lowering the Ca2+ concentration of the bathing medium from 2.5 mM to 1.25 mM during application of aconitine attenuated recovery and prevented the enhancement observed during washout of the drug. Application of aconitine in the presence of CdCl2 as well as in the presence of inhibitors of protein kinase C and Ca2+/calmodulin-dependent protein kinase II prevented the increase in spike amplitude during washout with standard artificial cerebrospinal fluid. In contrast, the N-methyl-d-aspartate (NMDA) receptor antagonists D-AP5 and MK-801 as well as the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione were ineffective in abolishing the aconitine-induced enhancement. These data support the conclusion that different modes of action are involved in the effects of aconitine but not veratridine. It is concluded that the aconitine-induced increase in neuronal activity is mediated by intracellular Ca2+-dependent mechanisms leading to an activation of Ca2+-dependent protein kinases. This effect is independent of Ca2+ entrance through NMDA and non-NMDA receptors.
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  • 47
    ISSN: 1432-1106
    Keywords: Key words Spinal cord ; Dorsal horn neuron ; Protein kinase C ; Pain modulation ; Periaqueductal gray ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of a protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), on the activity and periaqueductal gray (PAG)-induced inhibition of rat dorsal horn neurons of the lumbar spinal cord were tested. A microdialysis fiber was placed through the dorsal horn for the purpose of local application of pharmacological agents. Extracellular single-unit recordings from dorsal horn neurons were made near the microdialysis fiber. TPA was tested on nociceptive dorsal horn cells. There was a significant increase in the background activity and responses to ”brush”, with no changes in responses to pressure and pinch stimuli. TPA also significantly blocked the PAG-induced inhibition of responses to brush, press, and pinch. These effects were eliminated by coadministration of the PKC inhibitor NPC-15437. The solvent, which contained dimethyl sulfoxide, was also tested for its effect on the responses to peripheral mechanical stimuli and PAG-induced inhibition of the dorsal horn neurons. There were no significant changes. This experiment suggests that activation of the PKC second messenger system might increase the activity of dorsal horn neurons and their responses to peripheral stimuli; in addition, the phorbol ester attenuated the PAG-induced descending inhibition of the dorsal horn neuron activity.
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  • 48
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    Experimental brain research 117 (1997), S. 453-456 
    ISSN: 1432-1106
    Keywords: Key words Glutamate receptor subunits 2/3 ; 4 ; Neurectomy ; Hypoglossal nucleus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The immunoreactivity of glutamate receptor subunits 2/3 (GluR2/3) and 4 (GluR4) was studied following neurectomy of the hypoglossal nucleus (NH). After a short period of survival (at 1, 2, and 7 days postoperation, dpo), GluR2/3 immunoreactivity was barely dectectable in the operated side of HN. During these periods, GluR4 immunoreactivity was present, but was greatly reduced when compared with the GluR4 immunoreactivity in the unoperated side. The data suggest that of the 4 subunits of the AMPA receptor, GluR2/3 is the most susceptible receptor to the early stage of hypoglossal neurectomy, and GluR4 tolerated the lesion more than the others. It is also suggested that both GluR2/3 and 4 may play a very important neuroprotective role in the early stage of neuronal degeneration after axotomy, especially the former. Following a midterm survival period (14, 21, and 35 dpo), GluR2/3 immunoreactivity gradually reappeared in some neurons on the operated side of HN, which may indicate functional recovery. However, the number of GluR4-immunopositive neurons on the operated side of HN was greatly reduced. The reason for such a reduction is not known, but, from the speculative point of view, it is possible that the disappearance of GluR4-positive neurons may be related to their excitotoxic property, especially at 35 dpo, when neuronal cell death had already occurred. Following a long-term period of survival (i.e., 56, 90, and 120 dpo), the numbers of surviving neurons remained fairly constant, suggesting the possible cessation of neuronal death.
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  • 49
    ISSN: 1432-1106
    Keywords: Key words Entorhinal cortex ; Subiculum ; Retrohippocampus ; Latent inhibition ; Partial reinforcement extinction effect ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Experiment 1 assessed the effect of cytotoxic retrohippocampal (entorhinal and extra-subicular cortices) lesions on the development of latent inhibition (LI) using an off-the-baseline, between-subjects, conditioned emotional response paradigm. Sham-operated controls and unoperated rats that had been pre-exposed to a light stimulus prior to light-shock pairings showed less conditioned suppression towards the light stimulus than the nonpre-exposed animals, thus demonstrating LI. However, LI was not evident in rats with retrohippocampal lesions. In experiment 2, the same animals were trained to run in an straight runway for food. Half of the animals were trained under a 50% partial reinforcement schedule (i.e. they were rewarded randomly on half of the acquisition trials) and the other half were trained under a continuous reinforcement schedule (i.e. they were rewarded on every acquisition trial). When tested in extinction, animals trained on the partial reinforcement schedule showed greater persistence than animals trained on continuous reinforcement, thus demonstrating the partial reinforcement extinction effect (PREE). Rats with retrohippocampal lesions showed a PREE that was at least as clear as that seen in the sham-operated controls and in the unoperated animals. It is concluded that cytotoxic lesions of the retrohippocampal region selectively led to an abolition of LI, but spared the PREE. The present study thus provided evidence against the hypothesis that LI and the PREE share a common neural substrate.
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  • 50
    ISSN: 1432-1106
    Keywords: Key words Circumventricular organs ; Nitric oxide synthase ; Vasopressin ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The distribution of immunoreactivity to neuronal nitric oxide synthase (nNOS) and vasopressin (AVP) was studied in the circumventricular organs of the female rat. The occurrence of NOS immunoreactivity showed correspondence to nicotinamide dinucleotide phosphate diaphorase reactivity, a previously used but less specific marker for neuronal NOS. nNOS immunolabeling was detected in the two most rostrally located circumventricular organs – the organum vasculosum of the lamina terminalis and the subfornical organ. In the latter, AVP immunoreactivity was observed in some cell bodies, which also were nNOS-immunoreactive. In the median eminence and the neurohypophysis there were large amounts of nNOS- and AVP-immunoreactive nerve fibers, which often displayed similarities in distribution and morphology. Within the pineal gland, only very few nNOS-immunoreactive varicose terminals were observed, which ran along blood vessels. nNOS immunoreactivity was also seen in the epithelium of the choroid plexus, whereas no nNOS immunoreactivity could be found in the subcommissural organ or in the area postrema. The present demonstration of nNOS and AVP immunoreactivity in the subfornical organ, median eminence, and neurohypophysis, and the occurrence of nNOS immunoreactivity also in the choroid plexus and organum vasculosum of the lamina terminalis, provides a morphological background for a functional role for nitric oxide in water homeostatic mechanisms, both as executed through the hypothalamohypophyseal system and via the production of cerebrospinal fluid.
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  • 51
    ISSN: 1432-1106
    Keywords: Key words Hippocampus ; Commissural fibers ; Reactive sprouting ; Synaptogenesis ; Synaptophysin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Expression of the synaptic vesicle protein synaptophysin was studied in lesion-induced sprouting neurons of the contralateral entorhinal cortex and in the contralateral dentate gyrus using immunocytochemistry at the light- and electron-microscopic level. Perikaryal immunoreactivity for synaptophysin was found between 8 and 10 days postlesion. Light microscopy revealed that synaptophysin immunostaining was present in almost all neurons of layers II and III of the contralateral medial entorhinal cortex. These neurons give rise to the sprouting, crossed temporodentate pathway. In addition, some hilar neurons of the contralateral dentate gyrus, which are the parent cells of sprouting commissural fibers, were immunostained for synaptophysin. Transient immunostaining for synaptophysin was observed within cell bodies and dendrites. Additionally, the cell bodies were outlined by immunoreactive puncta, identified by electron microscopy as nerve terminals. Our results revealed that sprouting neurons express the major synaptic vesicle protein synaptophysin during reactive synaptogenesis in a pattern that reflects biosynthesis and sorting of this protein as seen in developing neurons during synapse formation.
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  • 52
    ISSN: 0942-0940
    Keywords: Rat ; brain injury ; diffuse injury ; free radicals ; lipid peroxidation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Free radicals are generated after head injury. These radicals rapidly react with polyunsaturated fatty acids in the cell membrane and cause membrane destruction. This process is called lipid per-oxidation. Malondialdehyde (MDA) is one of the end products of lipid peroxidation, and it is a frequently used indicator of lipid per-oxidation in biological tissues. Using a diffuse head injury animal model, we studied the time course of lipid peroxidation in different regions of injured rat brains. In the present study, the MDA levels were 36.7%, 41.8%, and 35.1% greater than sham at one hour after injury at the frontal, parietal, and brain stem, respectively (p〈0.0001). The MDA levels in these regions continued to increase and peaked a 4 hours after the injury. The levels slowly decreased, and by 24 hours, they were still significantly higher than the sham control's. The elevation of MDA levels was less in the striatum and the temporal regions at one hour. They were 16.9% and 13.3%, respectively (p〈0.002). The MDA levels in these two regions continued to increase even after 4 hours of injury, but the degree of elevation never exceeded 35%. The results demonstrate that there is an immediate, posttraumatic burst of MDA production, suggesting the formation of free radicals after diffuse head injury. Even though all the regions sampled show the same effect, certain regions are less affected by this diffuse head injury animal model.
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  • 53
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    European journal of plastic surgery 20 (1997), S. 136-140 
    ISSN: 1435-0130
    Keywords: Burn injury ; Stress protein ; HSP72 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to understand the stress response of systemic organs to severe burn injury, the induction of 72-kD heat shock protein (HSP72) in various organs (brain, hypophysis, lung, heart, liver, pancreas, spleen, kidney, adrenal gland, and skeletal muscle) was investigated in rats with severe burns. A full-thickness burn was induced on the rats' skin by immersing the rats in hot water (90° C) for 3 s. At 0, 24, and 48 h after the burn injury, the HSP72 expression of various organs was examined using the Western blot analysis. At 24 h after the burn injury, the level of HSP72 had increased in the hypophysis, lung, heart, and kidney. In all organs examined, the expression of HSP72 had increased at 48 h after the burn injury. The level of HSP72 was highest in the hypophysis (3.3-fold compared to the control), and lowest in the brain and adrenal gland (1.7-fold of the control) at 48 h after the burn injury. These results confirm that severe burn injury causes a stress response in systemic organs.
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  • 54
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    European archives of oto-rhino-laryngology and head & neck 254 (1997), S. 115-119 
    ISSN: 1434-4726
    Keywords: External auditory canal ; External otitis ; Pathogenesis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract External otitis was produced in 12 Sprague-Dawley rats by mechanical stimulation through a plastic micropipette inserted into the right external auditory canal (EAC). The EAC was later evaluated regarding the color of the skin, swelling and the presence of fluid. Within 1 day all rats developed an external otitis that was characterized by a red, swollen ear canal containing an opalescent fluid. The tympanic membrane and middle ear cavity appeared to be normal. No healed EACs were seen within the initial 10 days of follow-up and 4 of 6 rats still exhibited external otitis at day 21. Light microscopy of biopsy specimens revealed pronounced edema of the dermis of the ear canal. Mast cells were more numerous in the early phase of the otitis present, although very few inflammatory cells were found in tissues despite the marked inflammatory reaction produced. Findings show that this animal model for external otitis can be used to investigate pathogenesis as well as to test various treatment strategies.
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  • 55
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    European archives of oto-rhino-laryngology and head & neck 254 (1997), S. 425-429 
    ISSN: 1434-4726
    Keywords: Tympanic membrane ; Myringotomy ; Myringosclerosis ; Fenspiride ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Earlier studies have revealed a relationship between the development of myringosclerosis and oxygen-derived free radicals. The latter can be blocked by the anti-inflammatory drug fenspiride. The present study was undertaken to test the ability of fenspiride to prevent myringosclerosis from developing during healing of the tympanic membrane. Myringotomized rats were treated with either topical applications or intraperitoneal injections of fenspiride for 12 days, after which the tympanic membranes were examined by otomicroscopy and studied histologically by light microscopy. Topically applied fenspiride was found to inhibit the development of sclerotic lesions, whereas intraperitoneal injections were ineffective.
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  • 56
    ISSN: 1432-0843
    Keywords: Key words Anthracyclines ; Daunorubicin ; Daunorubicinol ; Pharmacokinetics ; Rat ; Aging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Age-related differences in pharmacokinetics may be important in determining altered anthracycline cardiotoxicity in the senescent rat and also in older humans. This study examined the effect of aging on daunorubicin pharmacokinetics in the Fischer 344 rat. Daunorubicin 7.5 mg/kg was administered i.v. to 6-and 24-month-old male Fischer 344 rats and plasma and tissue sampling was performed over 168 h for assay of daunorubicin and daunorubicinol concentrations by high-performance liquid chromatography. Systemic clearance of daunorubicin was decreased in older compared to younger animals (56±4 versus 202±17 ml min-1 kg-1; P〈0.05). In addition, the area under the plasma daunorubicinol concentration/time curve was significantly increased in older rats. In the heart, the area under the concentration/time curve was significantly increased in senescence both in the case of daunorubicin (201±12 versus 86±4 μg h g-1; P〈0.05) and daunorubicinol (1347±118 versus 182±4 μg h g-1; P〈0.05). Furthermore, the peak mean concentrations of daunorubicin were increased in older compared to younger rats both in plasma (1078±82 versus 663±66 ng ml-1; P〈0.05) and in heart (27±1 versus 10±1 μg g-1; P〈0.05). This also was true for daunorubicinol in plasma (284±39 versus 168±27 ng ml-1; P〈0.05) and in myocardium (8.6±0.6 versus 2.4±0.2 μg g-1; P〈0.05). Following daunorubicin injection, the ratio of daunorubicinol to daunorubicin concentrations in tissues increased with time, particularly in plasma and heart in senescent rats. Thus, there are significant age-related changes in daunorubicin and daunorubicinol kinetics in the rat that could alter susceptibility to acute systemic toxicity and to chronic cardiotoxicity.
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  • 57
    ISSN: 1573-6903
    Keywords: Rat ; early development ; cerebral cortex ; hippocampus ; homocysteine seizures ; glutamate binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Specific [3H]glutamate binding to synaptic membranes from the cerebral cortex and hippocampus of 7-, 12- and 18-day-old rats was examined, both in control animals and during seizures induced by homocysteine. In the cerebral cortex a transient peak of glutamate binding was observed in 7-day-old group, whereas in the hippocampus it occurred in 12-day-old animals. Total specific [3H]glutamate binding was not influenced by preceding seizure activity in either of the age groups and both the studied regions. NMDA- and QA-sensitive glutamate bindings represent the highest portion of the total binding. Moreover, NMDA-sensitive binding in the cerebral cortex of 7-day-old rats is significantly higher as compared to the two more mature groups. The proportion of individual receptor subtypes on total binding in each age group was not influenced by preceding seizure activity. However, NMDA-sensitive binding in the hippocampus of 12-day-old rats, sacrificed during homocysteine-induced seizures, was significantly increased as compared to corresponding controls. In contrast to the effect of NMDA, AMPA, kainate and quisqualate which displaced to a different extent [3H]glutamate binding, homocysteine had no effect when added to membrane preparations. Similarly, [3H]CPP and [3H]AMPA bindings were not affected in the presence of homocysteine. It thus seems unlikely that homocysteine is an effective agonist for conventional ionotropic glutamate receptors. Its potential activity at some of the modulatory sites at the NMDA receptor channel complex or at metabotropic receptors has to be clarified in further experiments.
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  • 58
    ISSN: 1433-2981
    Keywords: Peripheral blood ; Progenitor cells ; Rat ; Stem cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The assay system for determination of haemopoietic progenitors in peripheral blood of rats is essen tial for potential studies on mobilisation and transplantation of circulating progenitor cells in a rat experimental model. This paper demonstrates the possibility of detection and quantification of pluripotent progenitors (Colony Forming Units-Spleen day 8-CFU-Sd8) and committed progenitors (Colony Forming Units Granulocyte Macrophage-CFU-GM and Burst Forming Units-Erythroid-BFU-E) in peripheral blood of rats in a steady state. For determination of CFU-Sd8 the ‘rat to mouse’ in vivo assay was used, and for committed progenitors in vitro assays on methylcellulose were employed. The CFU-Sd8 incidence ranged from 7.3 to 11.6/ml of rat blood, similar to that reported in literature for mice. The incidence of CFU-GM was found to be 59.7 ± 9.4/ml which is in the range of the literature data for mice, rabbits, dogs and humans. The incidence of BFU-E in rat peripheral blood was 4.3 ± 1/ml, which was relatively low, but could be also considered as comparable with some literature data for dogs and humans. The CFU-E were not detected by the technique used. These results confirmed the existence of circulatory blood pluripotent progenitors (CFU-Sd8) and committed (CFU-GM and BFU-E) progenitors in rat, as has been established for some other mammalian species.
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  • 59
    ISSN: 1432-2013
    Keywords: Key words Mast cells ; Endothelial cells ; Cell adhesion molecules ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Mast cell (MC)-mediated induction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and of E-selectin was studied in cultures of rat heart endothelial cells (EC) and human umbilical vein EC (HUVEC) respectively. MC induced VCAM-1 and E-selectin, but hardly any ICAM-1 in EC. Induction was not dependent on MC degranulation, but seemed to be provoked by constitutively released substances, other than histamine, from MC. Co-incubation of MC and EC, allowing for direct contact between the two cell types, was more potent in induction than MC co-incubated separately from EC using a permeable membrane. MC were less potent in induction than exogenous added cytokines or LPS. Induction of cell adhesion molecules in rat heart EC was MC-specific, since EC incubations with either rat cardiomyocytes or heart fibroblasts had no effect. The data show that rat MC, independent of degranulation, secrete mediators relevant for the induction of a specific set of EC adhesion molecules in vitro. This suggests a (supportive) role for MC in cell-adhesion molecule induction in the endothelium in settings of early or mild inflammation. The results are discussed in the context of inflammatory processes in the heart in vivo.
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  • 60
    ISSN: 1432-0533
    Keywords: Key words Parkinson’s disease ; Neural transplantation ; Allogeneic ; Major histocompatibility complex antigens ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Neural transplantation, as a therapeutic approach to Parkinson’s disease, still requires allogeneic graft material and raises questions of immunosuppression and graft rejection. The present study investigated the time course of major histocompatibility complex (MHC) expression and astrocytic response in allogeneic dopaminergic grafts, comparing two different grafting protocols. Adult 6-hydroxydopamine-lesioned Lewis 1.W rats received intrastriatal cell suspension grafts from the ventral mesencephalon of DA rat fetuses, either as single 1-μl macrograft via metal cannula or as four micrografts of 250 nl/deposit via a glass capillary. No immunosuppression was administered. Immunohistochemistry was performed at 1, 3, 6, and 12 weeks after grafting, using antibodies against donor- and host-specific MHC class I and II antigen, glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH). Most animals showed good allograft survival up to 12 weeks after transplantation with no signs of rejection. Reinnervation of the lesioned striatum by TH-positive neurites was observed from 3–6 weeks on. Expression of donor-specific MHC class I was comparably low in both allogeneic grafting groups, while host MHC class I and II reaction as well as astrocytic response tended to be higher in the macrografted animals. Donor MHC class II was not observed at any time point. It is concluded that intraparenchymal allografts of fetal mesencephalic cell suspensions can survive well in the rat Parkinson model without immunosuppression for at least 12 weeks, and that the expression of moderate amounts of donor-specific MHC class I antigen does not suffice to initiate a rejection process. In addition, the microtransplantation approach may reduce the level of trauma and subsequent MHC and GFAP expression and may, thereby, minimize the risk of graft rejection.
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  • 61
    ISSN: 1432-2013
    Keywords: Key words Baroreceptor reflex ; Rostral ventrolateral medulla ; C1 cell group ; In vivo voltammetry ; Sino-aortic deafferentation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To test in a catechol-specific and dynamic manner for the existence of a powerful long-lasting inhibition arising from barosensitive afferents that depresses the activity of adrenergic neurons in the rostral ventrolateral medulla (RVLM), in vivo voltammetry was used before and after acute sino-aortic deafferentation. Rats were anaesthetized with pentobarbital or halothane and ventilated with a mixture of air and oxygen. Snares were inserted around the vagus, the glossopharyngeal and the superior laryngeal nerves. After placing the animal prone in the stereotaxic frame and stabilization at a high mean arterial pressure (MAP ≈ 120 mmHg), the snares were rapidly closed to produce complete barodeafferentation, assessed by loss of heart rate responses and changes in renal nerve sympathetic activity in response to vasoactive agents. Recording of a catechol signal was maintained in the RVLM during deafferentation. Under pentobarbital-induced anaesthesia (n = 5), deafferentation did not lead to a significant change in the catechol signal within the deafferented group. Under halothane-induced anaesthesia and phenylephrine-induced high baseline pressure (n = 5), no changes in the catechol signal were observed upon deafferentation (not significant vs sham animals: n = 5). This failure to demonstrate a major increase in catechol activity upon deafferentation does not fit with the hypothesis that a powerful tonic baroreflex-mediated inhibition depresses the activity of adrenergic RVLM barosensitive bulbospinal neurons, even when the baseline MAP is high. Rather, these data are compatible with weak or no inhibition of catechol activity by the baroreceptors and a nonessential role of adrenergic neurons within the baroreceptor reflex arc itself: the adrenergic neurons may not be in series within this arc but in parallel with the arc. This interpretation is in keeping with newer schemas of autonomic core circuitry that are devoid of adrenergic neurons.
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  • 62
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    Pflügers Archiv 434 (1997), S. 438-444 
    ISSN: 1432-2013
    Keywords: Key words Baroreceptor reflex ; Nucleus tractus solitarii ; Neonatal ; Maturation ; Cardiac vagal tone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ontogenesis of both vagal control of heart rate and the baroreceptor vagal reflex were evaluated in rats at postnatal ages (P) of 5/6, 10, 15, 20, 25 and 〉42 days anaesthetised with urethane (1.5 g/kg). Between P5/6 and P25 heart rate rose from 372 ± 12 to 448 ± 20 beats per minute and mean arterial pressure increased from 33.9 ± 3.1 to 74.59 ± 3.25 mm Hg (mean ± SEM, n = 7 and 11 respectively). Cardiac vagal tone was absent at P10 but significant at P20 (P 〈 0.05) as revealed with atropine (0.5–1 mg/kg i.v.). Baroreceptor cardiac reflex sensitivity, tested with phenylephrine (10–50 μg/kg i.v.), was attenuated significantly in P10–20 rats compared with P5/6, P25 and mature animals. In P14–17 rats stimulation of neurones in either the solitary tract or ambiguual nuclei, by microinjection of L-glutamate (100–200 pmol), evoked an atropine-sensitive bradycardia indicating a functional integrity of central and peripheral efferent pathways mediating the baroreceptor reflex. Thus, the baroreceptor vagal reflex is functional in P5/6 rats but becomes attenuated between P10–P20, which is coincident with the maturational rise in arterial pressure.
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  • 63
    ISSN: 1432-1912
    Keywords: Key words γ2-MSH (γ2-melanocyte-stimulating ; hormone) ; Blood pressure ; Heart rate ; Prazosin ; Metoprolol ; SR 49059 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract γ2-Melanocyte-stimulating hormone (γ2-MSH) and related melanotropins have been shown to have various cardiovascular effects, including acute, short-lasting increases in blood pressure (MAP) and heart rate (HR). γ2-MSH, administered intravenously, dose-dependently increased MAP and HR with an ED50 of approximately 30 nmol/kg and a maximal effect on MAP of approximately 55 mm Hg and on HR of around 70 beats per minute. Intravenous (i.v.) pretreatment with the α1-adrenoceptor antagonist, prazosin, caused the dose-response curve for the effect of γ2-MSH on MAP to shift to the right with a decrease in slope, whereas it had no effect on the dose-response curve for the effect on HR. I.v. pretreatment with the β1-adrenoceptor antagonist, metoprolol, had no effect on the dose-response curve for the effect of γ2-MSH on MAP, but it caused the dose-response curve for the effect of the peptide on HR to shift to the right with a decrease in slope. Neither i.v. nor intracerebroventricular (i.c.v.) administration of the vasopressin V1A receptor antagonist, SR 49059 ((2S) 1-[(2R 3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide), had significant effects on the dose-response curves for the effects of the peptide on either MAP or HR. The doses of prazosin, metoprolol and SR 49059 were found to be effective in counteracting the effects of agonists for these receptors (phenylephrine, isoprenaline and [Arg8]vasopressin, respectively). Taken together, these results support the postulate that the effects of γ2-MSH are, at least partially, due to an increase in sympathetic outflow to the periphery (Gruber and Callahan (1989), Am J Physiol 257: R681-R694), and that this increase leads to increased activation of vascular α1-adrenoceptors and cardiac β1-adrenoceptors. If, as was suggested by these authors, γ2-MSH acts via activation of a central vasopressin system, it is via a vasopressin receptor subtype other than the vasopressin V1A receptor, since i.c.v. administration of a selective vasopressin V1A receptor antagonist failed to interfere with the pressor and cardioaccelerator effects of γ2-MSH.
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  • 64
    ISSN: 1432-1912
    Keywords: Key words N-Methyl-D-aspartate (NMDA) antagonists ; Locomotion ; Stereotypy ; Catalepsy ; Basal ganglia ; Dopamine antagonists ; Dopamine metabolism ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of systemic administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonists dextrorphan (10–40mg/kg, i.p.) and [±]-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine (ADCI) (25–70mg/kg, i.p.) on basal ganglia-mediated behaviour and on forebrain dopamine metabolism were investigated in rats. Dextrorphan increased locomotor activity but did not induce stereotyped sniffing. ADCI failed to produce any significant motor stimulant and motor depressant actions. Both dextrorphan and ADCI dose-dependently antagonized catalepsy induced by the D-1 dopamine receptor antagonist SCH 23390 or the D-2 dopamine receptor antagonist haloperidol. Only the highest doses of dextrorphan and ADCI increased dopamine metabolism in the prefrontal cortex and/or in the nucleus accumbens, but not in the dorsal striatum. Our results show that dextrorphan and ADCI produce some of the behavioural effects (antagonism of experimentally induced catalepsy) and neurochemical actions (regionally selective stimulation of dopamine metabolism) that have previously been observed in the prototypical non-competitive NMDA antagonist, dizocilpine. The failure of ADCI to induce hyperlocomotion and stereotypy suggests that anticataleptic doses of ADCI may be devoid of the psychotomimetic actions commonly associated with non-competitive blockade of NMDA receptor function.
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  • 65
    ISSN: 1432-1912
    Keywords: Key words Daily rhythms ; Heart rate ; Temperature ; Locomotor activity ; Anaesthesia ; Ether ; Ketamine ; Rat ; Telemetry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to evaluate the effect of anaesthesia (ether or ketamine) on daily rhythms of temperature (T), heart rate (H) and locomotor activity (A) in unrestrained rats by using implanted radio-telemetry transmitters. T, H and A were measured every 10min, in Wistar male rats, and analysed using Cosinor. The mean±SEM days needed, after surgical implantation, to detect a daily rhythm in H, T and A were also assessed. Six rats were anaesthetized for about 50min either by ketamine or ether in a 3 by 3 cross-over design. Mesors, amplitudes and acrophases of T, H and A were calculated three days before (D-3; D-2; D-1), the day of anaesthesia (D0) as well as the three following days (D1; D2; D3). ANOVA was performed in order to detect, firstly a possible effect due to the order of application of anaesthesia, secondly a significant difference between ether or ketamine-induced anaesthesia and finally a modification of the mesors, amplitudes and acrophases of T, H and A, induced by each anaesthesia, for D0, D1, D2 and D3 when compared to D-1. Our results indicate: (1) Alterations of the acrophases, mesors and amplitudes, except for the amplitude of A, of the daily rhythms of T, H and A on D0 of ketamine anaesthesia while regarding ether anaesthesia only amplitude of T and H and acrophase of A were modified on D0. Some of these modifications were still observed on the days following anaesthesia. A significant difference between ether and ketamine-induced anaesthesia was also observed. (2) A non-detection of T, H and A daily rhythms after surgical implantation, which was not observed after injection of either ether or ketamine alone. Almost 10 days were needed to detect a significant daily rhythm for T, H and A. The authors suggest that, the general anaesthetic agent was responsible for a perturbation of the mesors, amplitudes and acrophases of the daily rhythms of H, T and A while the non-detection of these rhythms after implantation was more due to the surgical aggression.
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  • 66
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    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 297-302 
    ISSN: 1432-1912
    Keywords: Key words Lipid peroxidation ; Free radicals ; Oxidative stress ; In vitro ; In vivo ; Antioxidant ; Antiestrogen ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of the present study was to investigate antioxidativity of the triphenylethylene antiestrogen toremifene. Toremifene and its structural analogues were studied for their ability to inhibit chain reactions of lipid peroxidation and to act as scavengers of free radicals in vitro, and the effects of toremifene were compared to those of the estrogens, tamoxifen and known antioxidants. Moreover, the in vivo antioxidativity of toremifene was tested in a long-term experiment with rats. The ability of toremifene to prevent lipid peroxidation was assayed in two different test systems. In the first assay (initiated with ascorbate/ADP-FeCl3, detection by the formation of TBA-reactive material) toremifene was found to act as an efficient membrane antioxidant with an IC50-value (18 μM) comparable to that of tamoxifen (26 μM) and α-tocopherol (43 μM). Toremifene derivatives 4-hydroxytoremifene (IC50 = 8 μM) and Fc 1159 (IC50 = 31 μM), as well as diethylstilbestrol (IC50 = 17 μM) were also active while estradiol showed only weak antioxidativity (IC50 = 300 μM) in this test system. In the other assay (peroxidation initiated with t-butylhydroperoxide, detection by luminol-enhanced chemiluminescence) toremifene prevented lipid peroxidation only at high concentrations (IC50 = 450 μM) but the metabolite 4-hydroxytoremifene (IC50 = 0.18 μM), estradiol (IC50 = 4.6 μM) and diethylstilbestrol (IC50 = 1.7 μM) showed potent antioxidant activity. The potency of 4-hydroxytoremifene even exeeded that of α-tocopherol (IC50 = 2.0 μM) and butylated hydroxyanisole (IC50 = 1.1 μM). Toremifene was found to have some superoxide anion but no peroxyl radical scavenging activity. Interestingly, diethylstilbestrol turned out to be a potent scavenger of peroxyl radicals. Treatment of female Sprague-Dawley rats with toremifene (12 or 48 mg/kg) was found to decrease serum levels of lipid peroxides. This was seen at various time points (2 days, 5 weeks, 6 and 12 months) during long-term administration of toremifene to rats, and results obtained with two different methods (diene conjugation, TBA-reactive material) gave similar results. The present study thus showed that (i) like steroidal estrogens and tamoxifen toremifene is a potent membrane antioxidant in vitro, (ii) the antioxidant action of toremifene is not due to scavenging of free radicals and, importantly, (iii) toremifene acts antioxidatively also in living organisms in vivo.
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  • 67
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    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 341-347 
    ISSN: 1432-1912
    Keywords: Key words Complex partial seizure ; Diphenylhydantoin ; Epileptic focus ; Limbic system ; Rat ; Threshold
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Phenytoin is a major antiepileptic drug for treatment of limbic seizures. The effect of phenytoin on the generation and spread of seizure activity was studied in a rat model of this type of seizures. Sprague-Dawley and Wistar rats were implanted with a stimulation and recording electrode in the basolateral amygdala. Naive Sprague-Dawley rats showed an increase in current intensity necessary for eliciting afterdischarges (afterdischarge threshold) of about 200% after administration of phenytoin (75 mg/kg i.p.), while seizure severity at threshold was increased compared to controls. Afterdischarge and seizure durations were significantly prolonged under phenytoin. This result suggests that phenytoin can exert a potent anticonvulsant effect on the generation of focal seizure activity, but it does not suppress or may even increase on-going afterdischarge activity once it occurs. Following amygdala kindling in Wistar rats, administration of phenytoin again resulted in an increase in the afterdischarge threshold. However, all rats still showed generalized seizures, and epileptic afterdischarges could be recorded in various limbic brain regions at threshold current. This result suggests that phenytoin can increase the threshold for generation of epileptic discharges in kindled rats, but is not able to prevent the development of generalized seizure activity and the spread of afterdischarges within the limbic system when focal activity is initiated. We conclude that phenytoin is able to suppress focal seizure activity in the amygdala kindling model of the rat. However, it does not prevent the spread of seizure activity originating in the limbic system. Therefore, a decrease in focal seizure susceptibility seems to be the primary target for phenytoin’s anticonvulsant action.
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  • 68
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    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 364-367 
    ISSN: 1432-1912
    Keywords: Key words Capsaicin ; CGRP (calcitonin ; gene-related peptide) ; Endothelium-dependent ; relaxation ; Thoracic aorta ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have shown that pretreatment with calcitonin gene-related peptide (CGRP), a principal transmitter in sensory nerves, can protect the endothelial cell. We therefore evaluated whether in vivo capsaicin treatment prevents endothelial damage elicited by lysophosphatidylcholine (LPC) in the rat aorta. Acute treatment or repeated pretreatment with capsaicin resulted in stimulation of neurotransmitter release from sensory nerves or depletion of their transmitter content respectively. Vasodilator responses to acetylcholine (ACh) were examined in the aorta of these animals. Acute application of capsaicin (50 mg/kg) increased the plasma concentration of CGRP-like immunoreactivity (CGRP-LI) concomitantly with a reversal of the inhibition by LPC of endothelium-dependent ACh-induced relaxation in the isolated rat aorta. After repeated pretreatment with capsaicin to deplete sensory nerve neurotransmitter content the effects of capsaicin were absent as shown by the plasma CGRP-LI concentration and the vasodilator response to ACh. The results demonstrate that systemic capsaicin treatment, which evokes the release of CGRP from sensory nerves, protects the endothelial cell. The present study also suggests that CGRP may be an endogenous vascular protective substance.
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  • 69
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    Naunyn-Schmiedeberg's archives of pharmacology 355 (1997), S. 689-698 
    ISSN: 1432-1912
    Keywords: Key words β-adrenoceptors ; β adrenoceptor antagonists ; Celiprolol ; Rat ; Blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Celiprolol is a β-adrenoceptor antagonist which has desirable ancillary properties since it is relatively cardioselective and can exert direct vasodilator and bronchodilator effects. Here agonist and antagonist effects of celiprolol at cardiac β1- and vascular β2-adrenoceptors were determined under in vivo conditions in the rat. All experiments were carried out in catecholamine-depleted, pentobarbital anesthetized and vagotomized rats, placed under artificial respiration. I.v. administrations were madevia the femoral vein. Blood pressure was measured from the cannulated right carotid artery and heart rate was recorded with a cardiotachometer. Celiprolol (10 µg/kg to 1 mg/kg i.v.) produced dose-related increases in heart rate and decreases in mean carotid artery blood pressure which were of longer duration than those mediated by standard agonists of β1-(isoprenaline) or β2-(salbutamol) adrenoceptors respectively. Although the maximal increase in heart rate by celiprolol (110±4 beats/min, n=7) was approximately half that of isoprenaline (198±1 beats/min, n=5), isoprenaline acted at doses 200-fold lower than celiprolol. Betaxolol (0.03-0.3 mg/kg i.v.), a β1-adrenoceptor antagonist, inhibited strongly and with similar potency the tachycardic effects of celiprolol (DR10 = 45 µg/kg i.v.) as well as isoprenaline (DR10 = 45 µg/kg i.v.). On the other hand, the hypotensive effects of celiprolol and salbutamol were antagonized markedly and with similar potency by ICI118,551, a relatively selective β2-adrenoceptor antagonist (DR10 = 15 and 25 µg/kg i.v. respectively). In rats pretreated with celiprolol (0.03 to 0.3 mg/kg i.v.), the heart rate dose-response curves to isoprenaline were shifted to the right of those determined in matched groups of vehicle-pretreated animals. In this respect, celiprolol was half as potent as betaxolol in blocking cardiac β1-adrenoceptors. Furthermore, celiprolol also antagonized the hypotensive effects of salbutamol, but, in this respect, celiprolol was 90-fold less potent than ICI 118,551. In conclusion, these results clearly indicate that celiprolol has the ability of stimulating and blocking not only cardiac β1- but also vascular β2-adrenoceptors. The effects on cardiac β1-adrenoceptors as well as the agonism of β2-adrenoceptors are produced by similar doses of celiprolol. These doses are notably lower than those necessary to block β2-adrenoceptors. Thus, this pharmacological profile, which has also been demonstrated in humans, indicates that celiprolol is a modulator of cardiac β1-adrenoceptors with vascular β2-adrenoceptor agonist properties.
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  • 70
    ISSN: 1432-1912
    Keywords: Key words Urinary bladder ; Hyperreflexia ; Tachykinin antagonists NK1 receptors ; Tachykinin antagonists ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study investigates the role of tachykinin NK1 and NK2 receptors in motor responses induced by the intravesical instillation of capsaicin in urethane-anaesthetized rats. SR 140,333 (1 µmol/kg, i.v.), a non-peptide NK1 receptor antagonist, abolished urinary bladder contractions induced by the selective NK1 receptor agonist [Sar9]SP-sulfone (0.1-100 nmol/kg, i.v.) without affecting those induced by the NK2 receptor agonist [ßAla8]NKA(4-10). MEN 11,420 (100 nmol/kg, i.v.), a cyclic peptide NK2 receptor antagonist, abolished bladder contractions induced by [ßAla8]NKA(4-10) (0.3-300 nmol/kg, i.v.) without modifying those induced by [Sar9]SP-sulfone. Intravesical instillation of capsaicin (6 nmol/0.6 ml/rat) produced a motor response consisting in a primary contraction followed by a series of high amplitude phasic contractions. The intravesical instillation of saline (0.6 ml/rat) produced a primary contraction of lower amplitude with respect to that induced by capsaicin and the total area under the curve was also lower in saline-instilled rats, however the number and the amplitude of phasic contractions was similar to that induced by capsaicin. MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline. In contrast, in capsaicin-instilled rats, MEN 11,420 (100 nmol/kg, i.v.) reduced the primary contraction, the area under the curve and also the number of phasic contractions. SR 140,333 (1 µmol/kg, i.v.) reduced the primary contraction but not other parameters. The combination of SR 140,333 (1 µmol/kg, i.v.) and MEN 11,420 (100 nmol/kg, i.v.) produced an additive inhibitory effect on the primary contraction but not a further inhibition on other parameters with respect to that observed with MEN 11,420 alone. In hexamethonium (110 µmol/kg, i.v.)-pretreated animals the intravesical instillation of capsaicin produced a tonic contraction having greater amplitude and area than that induced by saline. MEN 11,420, but not SR 140,333, significantly reduced the bladder response to capsaicin in hexamethonium-pretreated rats. Again, the combined administration of MEN 11,420 and SR 140,333 did not produce further inhibitory effect in comparison to MEN 11,420 alone. It is concluded that the motor responses induced by the intravesical instillation of capsaicin are mediated by the activation of peripheral tachykinin NK2 receptors.
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  • 71
    ISSN: 1432-1912
    Keywords: Key words [3H]-Acetylcholine release ; Rat ; caudatoputamen ; Cholinergic interneurons ; Glycine ; receptors ; Serine ; Strychnine ; Ethanol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present study acute effects of ethanol on [3H]-acetylcholine ([3H]-ACh) release induced by activation of strychnine-sensitive glycine receptors in superfused slices of rat caudatoputamen were investigated. The glycine-evoked [3H]-ACh release (lg EC50 = –4.10, CI95 = [–4.14, –4.05]) was inhibited by strychnine in a competitive manner (pA2 = 6.86, CI95 = [6.61, 7.08]). Release of [3H]-ACh could also be induced by L-serine. L-serine was less potent than glycine (lg EC50 = –2.61, CI95 = [–2.69, –2.52]). Both glycine and L-serine showed similar maximum effects (Emax(glycine) = 1.34, CI95 = [1.24, 1.45]; Emax(L-serine) = 1.19, CI95 = [1.09, 1.32]). Ethanol at concentrations of 2‰ (= 34 mM) and 4‰ (= 68 mM) inhibited glycine-evoked [3H]-ACh release in a manner like the competitive antagonist strychnine, however with lower potency. The pA2 of ethanol was 1.19, CI95 = [0.85, 1.41], at 2‰ [v/v] and 1.51, CI95 = [1.19, 1.78] at 4‰ ethanol. Similar to its action on glycine-evoked [3H]-ACh release, ethanol at 4‰ [v/v] also inhibited L-serine-evoked transmitter release in a competitive-like fashion (pA2 = 0.83, CI95 = [–0.15, 1.18]). We conclude, that strychnine-sensitive glycine receptors, mediating [3H]-ACh release in the rat caudatoputamen, might represent a new site of action of ethanol.
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  • 72
    ISSN: 1432-1912
    Keywords: Key words Neuropeptide Y (NPY) ; Ca2+ efflux ; Y1 receptor ; Na+/Ca2+ exchange ; Na+ influx ; Cardiomyocyte ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several physiological stimuli cause a rise in intracellular Ca2+ concentration ([Ca2+]i) in cardiomyocytes. This increased [Ca2+]i must be restored to physiological resting level to ensure response to further stimuli. In the present study, we examined the effect of neuropeptide Y (NPY), which is secreted from certain adrenergic or non-adrenergic neurons, on Ca2+ efflux from freshly isolated, quiescent adult rat cardiomyocytes. The isolated cardiomyocytes were preloaded with 45CaCl2 for 1 h. Then, the fractional release of 45Ca2+ from the cells was measured. NPY stimulated the efflux of 45Ca2+ from isolated adult rat cardiomyocytes in a concentration-dependent manner (10–8 M to 10–6 M). NPY (10–6 M)-induced Ca2+ efflux was 2.0 ± 0.16% of the total cellular content. The 45Ca2+ efflux from the cells was also stimulated by Y1 receptor agonist, [Leu31, Pro34]NPY, but not by Y2 receptor agonist, NPY13–36. The effect of NPY was inhibited by a peptide NPY inhibitor, NPY18–36 and a non-peptide NPY inhibitor, benextramine to a similar extent. From these results, it is conceivable that the effect of NPY on Ca2+ efflux from cardiomyocytes is mediated through Y1 receptors. It was also observed that NPY caused a rise in [Ca2+]i to almost 150 nM. NPY-stimulated 45Ca2+ efflux was not affected by removal of extracellular Ca2+, but was dependent on the presence of extracellular Na+. Moreover, NPY caused a 22Na+ influx into the cells of about 1.6-fold over the basal value which was inhibited by amiloride and 5-(N,N-dimethyl)-amiloride, known Na+/Ca2+ exchange inhibitors. In addition, isoproterenol also caused 45Ca2+ efflux from the cells and which was enhanced by the addition of NPY. These results suggest that NPY stimulates extracellular Na+-dependent 45Ca2+ efflux from freshly isolated adult rat cardiomyocytes, probably through its stimulatory effect on plasma membrane Y1 receptors with which NPY may couple during Na+/Ca2+ exchange.
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  • 73
    ISSN: 1432-1912
    Keywords: Key words Morphine ; Nitric oxide ; Apomorphine ; Oxytocin ; Penile erection ; Yawning ; Paraventricular nucleus of the hypothalamus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The possible involvement of nitric oxide in the prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning was investigated by measuring the concentration of NO2- and NO3- in the dialysate obtained with a vertical microdialysis probe implanted in the paraventricular nucleus of the hypothalamus of male rats. Either apomorphine (80 µg/kgs.c.) or oxytocin (30 ng i.c.v.) increased significantly basal NO2- and NO3- concentration in the paraventricular dialysate, penile erection and yawning. Morphine (1, 5 and 10mg/kg i.p.) prevented dose-dependently either apomorphine or oxytocin responses when given 15min before apomorphine or oxytocin. Prevention by morphine of apomorphine and oxytocin responses was abolished by naloxone (3mg/kg i.p.) given 15min before morphine. Morphine prevented apomorphine and oxytocin responses also when given in the lateral ventricles or directly in the paraventricular nucleus. In contrast, the selective agonist of the kappa opioid receptor subtype U-69,593 was found to be ineffective. The present results confirm previous findings showing that morphine acts through µ receptors in the paraventricular nucleus to prevent apomorphine and oxytocin-induced penile erection and yawning and suggest that this morphine effect is mediated by a decreased activity of nitric oxide in the paraventricular nucleus of the hypothalamus.
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  • 74
    ISSN: 1432-1912
    Keywords: Key words Blood pressure ; GR127935 ; Hypotension ; 5Hydroxytryptamine ; 5ht7Receptor ; Rat ; Sumatriptan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been suggested that the late hypotensive response to serotonin (5hydroxytryptamine; 5HT) in vagosympathectomized rats is mediated by ‘5HT1like’ receptors since this effect is mimicked by 5carboxamidotryptamine (5CT), is not modified by cyproheptadine, ketanserin or MDL72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NCIUPHAR subcommittee on the classification and nomenclature of 5HT receptors. I.v. bolus injections of 5CT (0.010.3μg·kg1), 5HT (130μg·kg1) and 5methoxytryptamine (5MeOT; 130μg·kg1) produced dosedependent hypotensive responses with a rank order of agonist potency: 5CT 〉〉 5HT ≥ 5methoxytryptamine with sumatriptan (301000μg·kg1) inactive. The depressor responses to 5HT and 5CT were not attenuated by i.v. GR127935 (3003000μg·kg1) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5HT and 5CT; the rank order of apparent pA2 values against 5HT and 5CT, respectively, was: lisuride (7.7; 7.8) 〉 methiothepin (6.8; 7.0) ≥ mesulergine (6.4; 6.6) 〉 clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenalineinduced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5ht7 receptor and the lack of blockade by GR127935, our results indicate that the 5HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5ht7 receptors mediating vascular and nonvascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guineapig ileum as well as feline tachycardia).
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  • 75
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    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 166-172 
    ISSN: 1432-1912
    Keywords: Key words Catalepsy ; VM nucleus ; Kainic lesions ; Pontine reticular formation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bilateral kainic acid lesions of the ventro-medial (VM) thalamic nucleus of rats which greatly reduced the catalepsy produced by haloperidol (2 mg/kg i.p.) not only did not reduce, but even enhanced, the cataleptogenic effect of eserine (1 mg/kg i.p.) and arecoline (30 mg/kg i.p.). This finding is in accord with former conclusions that catalepsy produced by cholinergic drugs does not depend on striatal mechanisms. In rats with kainic acid lesions of the VM thalamic nucleus, and similarly in intact, non-lesioned rats, systemic administration of eserine and arecoline potentiated the catalepsy produced by microinjections of carbachol (2 μg) into the pontine reticular formation (PRF). Atropine microinjected bilaterally into the PRF attenuated the cataleptogenic effect of eserine and arecoline i.p. We suggest that the PRF is a site at which systemically given cholinergic drugs act to produce catalepsy.
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  • 76
    ISSN: 1432-1912
    Keywords: Key words 5-Hydroxytryptamine ; 5-HT1A receptors ; Microdialysis ; Flesinoxan ; WAY 100635 ; 8-OH-DPAT ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The modulation of extracellular 5-hydroxytryptamine (5-HT) in the central nucleus of the amygdala (CeA) by 5-HT1A receptors was studied by intracerebral microdialysis in awake and freely moving rats. Local administration of 1 μM tetrodotoxin (TTX), 60 mM K+ and perfusion with Ca2+-free Ringer containing EGTA confirmed that the major part of dialysate 5-HT levels from the CeA is of neuronal origin. Administration of 300 nM of RU 24969, a 5-HT1B receptor agonist, through the probe into the CeA decreased dialysate 5-HT levels to 67.2% of the baseline value. Systemic administration of the 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan dose-dependently decreased 5-HT levels in the CeA. The effect of 0.3 mg/kg of flesinoxan could be completely antagonized by systemic administration of 0.05 mg/kg WAY 100635, a 5-HT1A receptor antagonist. WAY 100635 alone had only minimal effects at this dose. These data show that a major part of the extracellular 5-HT in the CeA stems from 5-HT neurons and that the amount of 5-HT released into this brain region can be modulated by 5-HT1A receptors.
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  • 77
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    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 611-618 
    ISSN: 1432-1912
    Keywords: Key words Hippocampus ; EPSP ; IPSP ; GABA ; NMDA ; Epilepsy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice preparation. Levetiracetam in a concentration of 10 μM did not influence basic cell properties or normal synaptic transmission evoked by subthreshold and suprathreshold stimuli to the commissural pathway. However, it strongly inhibited the development of epileptiform bursting by the γ-aminobutyric acid (GABA)A-receptor antagonist bicuculline (1– 30 μM). Levetiracetam also decreased the size of bursts previously established by bicuculline. In experiments in which the glutamate-receptor agonist N-Methyl-D-Aspartate (NMDA) was used to generate spontaneous bursting, levetiracetam had no effect on the size of the bursts but decreased bursting frequency. The difference in effects of levetiracetam on bicuculline- and NMDA-induced bursting appeared to be dependent on the convulsant used, since in the presence of 10 μM bicuculline, levetiracetam decreased the size of NMDA-bursts to the same extent as the size of synaptically evoked bicuculline-bursts but had little effect on bursting frequency. The results show that under our experimental conditions, levetiracetam did not alter the components of normal synaptic transmission. However, levetiracetam at the concentrations studied inhibited epileptiform bursting induced by bicuculline and NMDA in vitro in a manner consistent with the profile of an antiepileptogenic drug.
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  • 78
    ISSN: 1432-1912
    Keywords: Key words Neocortex ; Cholecystokinin ; Dynorphin ; Amino acids ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of sulphated cholecystokinin-8 (CCK-8S) on extracellular dynorphin B, aspartate, glutamate and GABA levels in the rat fronto-parietal cortex was investigated with in vivo microdialysis. The peptide was infused through the microdialysis probe trying to mimic local CCK-8S release. Basal levels of dynorphin B were around 20pM, aspartate 100nM, glutamate 600nM and GABA 30nM. CCK-8S (10μM) induced a ≈3-fold increase in extracellular dynorphin B, aspartate and glutamate levels, while GABA levels were only slightly increased. The effect of CCK-8S was restricted to the stimulated neocortex. Systemic pretreatment with the CCKB antagonist, L-365, 260, but not with the CCKA antagonist, L-364, 718, significantly antagonised the effect of CCK-8S on cortical dynorphin B and aspartate release. However, both CCKA and CCKB antagonists inhibited the increase in cortical glutamate levels. Thus, the present results indicate that cortical CCK release exerts a stimulatory modulation on cortical dynorphin B and aspartate release via the CCKB receptor subtype, and on glutamate release via both CCKA and CCKB receptor subtypes. Considering electrophysiological evidence that CCK increases neuronal firing rates in many brain regions, it may be suggested that CCK represents a stimulatory system modulating the function of the neocortex.
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  • 79
    ISSN: 1432-2072
    Keywords: Key words NNC 19-1228 ; NNC 22-0031 ; Dopamine ; Neuroleptic ; Behavioral models ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract NNC 19-1228 [1-(3(6-benzothiazolylcarbamoyloxy)propyl)-4-(6-flouro-1,2-benzisoxazol-3-yl)piperidine] and NNC 22-0031 [4-(6-flouro-1,2-benzisoxazol-3-yl)-1-(3-(3,4-methylenedioxyphenylcarbamoyloxy)propyl)piperidine] are newly developed compounds with an in vitro pharmacologic profile similar to that of clozapine, i.e., mixed dopamine (DA), 5-hydroxytryptamine (5-HT)2 and α1-adrenergic antagonist action. In pharmacological experiments in mice, the compounds inhibited DA D2 receptor binding in vivo at doses that produced only moderate antagonism of methylphenidate (MPD)-induced stereotyped gnawing. However, the compounds were markedly more potent in blocking MPD-induced motility, a model which showed a high degree of sensitivity to α1-adrenergic antagonism, but not 5-HT2 antagonism. In rats, the NNC-compounds blocked conditioned avoidance responding and attenuated the discriminative stimulus effects of amphetamine, but failed to induce catalepsy. These results are discussed in terms of adrenergic, serotonergic and dopaminergic interactions which suggest that the NNC compounds may act as DA antagonists with mesolimbic selectivity, and thus may have efficacy as antipsychotics without coincident extrapyramidal side effects.
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  • 80
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    Psychopharmacology 129 (1997), S. 249-256 
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Acute tolerance ; Ibogaine ; Dopamine ; Microdialysis ; In vivo ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is increasing evidence that the rewarding effect of nicotine is mediated by the mesolimbic dopamine system. The first objective of this study was to examine the dopamine response to repeated IV infusions of nicotine. Using in vivo microdialysis in awake and freely moving male Sprague-Dawley rats, we demonstrated that IV nicotine infusions (0.16 mg/kg or 0.32 mg/kg per infusion) produced increases in extracellular dopamine levels that were dose- and infusion order-dependent. Acute tolerance was evidenced by the smaller dopamine response produced by a second infusion of nicotine, administered 1 h after the first one. Tolerance was reversible, since the dopamine response to a second infusion of nicotine was unchanged when the interval between the infusions was increased to 3 h. Ibogaine, an alkaloid found in Tabernanthe iboga, is claimed to decrease smoking and to have an anti-nicotinic action. The second objective of this study was to establish whether this claim has any neurochemical basis. Pretreatment with ibogaine (40 mg/kg, IP) 19 h prior to the first nicotine infusion (0.32 mg/kg per infusion) significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusions, suggesting that ibogaine may decrease the rewarding effect of nicotine.
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  • 81
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Schizophrenia ; Dopamine ; Serotonin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The β-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (−)alprenolol, was found to potentiate the disrupting effect of the non-competitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (−)alprenolol. (−)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective β-adrenoceptor antagonist property of (−)alprenolol, since combined pretreatment with the β1- and β2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (−)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (−)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.
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  • 82
    ISSN: 1432-2072
    Keywords: Key words Hyperactivity ; Hippocampus ; Neonate ; Negative symptoms ; Positive symptoms ; Rat ; Schizophrenia ; Social behaviour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 μmol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
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  • 83
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Drug discrimination ; Dopamine (DA) ; Human ; Rat ; Reuptake inhibitor ; Reinforcing effects ; Self-administration ; Serotonin (5-HT) ; 5-HT1A ; 5-HT2 ; 5-HT3 ; Subjective effects ; Stimulus effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of the present manuscript is to review the current status of the role of serotonin (5-hydroxytryptamine; 5-HT) systems in the stimulus and reinforcing properties of cocaine in non-humans and the subjective effects of cocaine in humans. Review of the current literature suggests that general enhancement (via precursor administration) or depletion of brain 5-HT content (via neurotoxin administration or tryptophan depletion) impact the reinforcing effects of cocaine in non-humans and its subjective effects in humans. Selective 5-HT reuptake inhibitors (SSRIs) enhance the discriminability of cocaine and decrease cocaine self-administration in animals, although data to the contrary also exist. Studies in humans suggest that SSRIs attenuate the subjective effects of cocaine in humans. Although few drugs with selectivity for 5-HT2 receptors have been studied systematically, a 5-HT2 agonist and several antagonists show some efficacy in enhancing and reducing, respectively, the reinforcing effects of cocaine in non-humans. Limited data from humans suggest that a 5-HT2 antagonist may also decrease the subjective effects of cocaine; thus, 5-HT2 compounds deserve further attention. The majority of studies evaluating the 5-HT3 antagonists have reported negative results across all paradigms. In summary, while the functional significance of 5-HT receptors has not been fully elucidated, these data suggest that changes in serotonergic activity can modulate the effects of cocaine in both animals and humans under a variety of experimental conditions. One commonality among the studies with positive findings is that cocaine effects are only partially modified by 5-HT agents regardless of the direction of change.
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  • 84
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    Psychopharmacology 130 (1997), S. 79-84 
    ISSN: 1432-2072
    Keywords: Key words Latent inhibition ; Conditioned emotional response ; Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of a single administration of d-amphetamine (0.32 mg/kg, SC) upon latent inhibition (LI) in a one-session pre-exposure and conditioning procedure was investigated in rats in a conditioned emotional response paradigm. It was found that amphetamine attenuated LI. The effects could not be attributed to differences in unconditioned suppression nor to differences in response rates between the experimental groups. These results support the observations of Dunn and suggest that the disruption of LI may not depend upon a complex interaction between changes in neuronal processes consequent upon repetitive amphetamine administration and the schedule with which the drug is administered during the experimental procedure.
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  • 85
    ISSN: 1432-2072
    Keywords: Key words Buprenorphine ; Drug abuse ; Place preference ; Taste aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Buprenorphine, a mixed agonist-antagonist opioid with considerable analgesic activity, is currently indicated as a therapeutic agent with low abuse potential. Nevertheless, buprenorphine abuse has been recently reported from some countries. Thus the present experiments were performed to characterize further the motivational properties of buprenorphine in rats. Rewarding and aversive effects were assessed by place preference and taste aversion conditioning, respectively. It was found that buprenorphine (0.025, 0.050, 0.100 mg/kg SC) causes a significant increase in the amount of time spent on the conditioned side, but no significant decrease in saccharin consumption. Therefore buprenorphine data are not consistent with the general finding that psychoactive drugs cause rewarding and aversive effects within a similar dose range.
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    Psychopharmacology 130 (1997), S. 213-221 
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Rat ; Autoshaping ; Appetitive conditioning ; Posttraining ; Instrumental conditioning ; Classical conditioning ; Acquisition ; Memory ; Learning
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of daily peripheral (IP) post-session injection of cocaine on the development of an autoshaped lever-touch response in rats were investigated. Male Sprague-Dawley rats received ten daily pairings of a retractable lever (conditioned stimulus; CS) and food delivery (unconditioned stimulus; UCS). Food delivery occurred if the subjects contacted the extended lever within 10 s, or, if the subjects failed to contact the lever, at the end of the 10-s stimulus interval. These contingencies resulted in increased lever-touch responses over 10 days of conditioning. Cocaine (5.6–19.0 mg/kg) impaired development of the lever-touch response, as compared to saline-treated control subjects. Because the injections were given immediately after each conditioning session, we suggest that cocaine affects the neural processes involved in consolidation. Three additional control experiments support this suggestion. The effect of cocaine on lever-touch acquisition was time-dependent as daily injection of cocaine (5.6 mg/kg) 3 h after each conditioning session did not affect lever-touch acquisition. In addition, the effect of cocaine was dependent upon the explicit pairing of lever extension (CS) and food delivery (UCS) as immediate post-session cocaine (5.6 mg/kg) administration did not alter responding when the presentation of both the CS and the UCS was uncorrelated. Cocaine (5.6 mg/kg) administered to subjects previously trained to a performance criterion did not affect lever-touch responding, indicating that cocaine administration (5.6 mg/kg) impairs the development, but not the maintenance, of autoshaped lever-touch responding. In contrast, the highest dose of cocaine tested, 19.0 mg/kg, did decrease lever-touch responding in well-trained subjects, indicating that post-session administration of higher doses of cocaine can produce aversive effects that may affect both the acquisition and maintenance of appetitively motivated behavior in the rat. The relative contributions of the instrumental and classical associations inherent in the autoshaping procedure were investigated by altering response contingencies. Rats showed no evidence of learning the lever-touch response when lever insertion and food delivery were positively correlated, and no explicit response contingency was present (classical conditioning); further, cocaine-treated subjects did not differ from saline-treated subjects. However, cocaine did impair lever-touch responding in the instrumental version of the task. Taken together, these results show that the post-session administration of cocaine can impair the acquisition of a multi-trial, multi-session appetitively motivated response.
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  • 87
    ISSN: 1432-2072
    Keywords: Key words Working memory ; Motor activity ; Serotonergic ; Muscarinic ; Nicotinic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats.
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  • 88
    ISSN: 1432-2072
    Keywords: Key words Nitric oxide ; Prepulse inhibition ; Locomotor activity ; Schizophrenia ; Phencyclidine ; Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of the nitric oxide synthase inhibitor, N G-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system.
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  • 89
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    Psychopharmacology 134 (1997), S. 221-229 
    ISSN: 1432-2072
    Keywords: Key words Behavioral sensitization ; Dopamine ; Amphetamine ; Rat ; Microdialysis ; Caudate putamen ; Nucleus accumbens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The repeated administration of amphetamine (AMPH) results in a pattern of behavioral changes which includes an augmentation of some behaviors, generally referred to as behavioral sensitization. Some investigators have suggested that an increased dopamine (DA) response to AMPH challenge may underlie behavioral sensitization, while others have reported behavioral sensitization in the absence of an enhanced DA response. Because temporal and dosage parameters of the AMPH pretreatment regimen have been suggested to play a role in the appearance of an enhanced DA response, we utilized a variety of AMPH pretreatment regimens to assess the relationship between pretreatment dose of AMPH, duration of withdrawal and the DA response in caudate-putamen and nucleus accumbens to a subsequent AMPH challenge. Under our experimental conditions, behavioral sensitization was observed after each of these treatments in the absence of an enhanced DA response in either brain region.
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  • 90
    ISSN: 1432-2072
    Keywords: Key words Anxiety ; Mouse ; Rat ; Stretched attend posture ; Risk assessment ; Canopy ; Diazepam ; Chlordiazepoxide ; Ipsapirone ; Buspirone ; 8-OH-DPAT ; mCPP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioural element, stretched attend posture (SAP), is an important component of the “risk-assessment” repertoire of defensive behaviour in rodents. The present experimental paradigm was devised as a novel and simple method of eliciting high levels of SAP in mice and rats. The SAP test apparatus comprised an elevated black Perspex circular platform. A smaller clear red Perspex circular “Canopy” was supported directly above the platform by a central pillar, thus dividing the platform into an inner, dimly lit covered zone and an outer, brightly lit exposed zone. In both the rat and mouse version of this model, vehicle-treated animals exhibited a marked preference for exploring the covered zone and also exhibited high baseline levels of SAP, particularly at the covered zone boundary whilst they investigated the exposed zone. In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg SC) and chlordiazepoxide (2 mg/kg SC), and the 5-HT1A receptor agonists, buspirone (1 and 3 mg/kg SC), ipsapirone (3 mg/kg SC) and 8-OH-DPAT (0.2 mg/kg SC), all significantly decreased the frequency of SAP without impairing motor activity. In the rat SAP test, diazepam (0.5 mg/kg SC) significantly decreased, whilst the anxiogenic 5-HT2C/1B receptor agonist, mCPP (0.25 and 0.5 mg/kg SC), significantly increased, the frequency of SAP. Ipsapirone (3 mg/kg SC) induced a non-specific behavioural inhibition. These data suggest that the “Canopy” SAP test is a useful paradigm to investigate risk assessment behaviour in both rats and mice, and may provide a sensitive novel rodent model of anxiety.
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  • 91
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    Psychopharmacology 133 (1997), S. 51-54 
    ISSN: 1432-2072
    Keywords: Key words Conditioned taste aversion ; Lithium ; Serotonin ; 5-HT1A receptor ; 8-OH-DPAT ; Pindolol ; p-MPPI ; PCPA ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experiments were carried out using rats to investigate whether 5-HT1A neural mechanisms are involved in lithium-induced conditioned taste aversion (CTA). We found that the 5-HT1A antagonists p-MPPI and pindolol caused CTA similar to that produced by LiCl. The 5-HT1A agonist 8-OH-DPAT counteracted lithium-induced CTA. Pindolol dose-dependently abolished effects of 8-OH-DPAT on LiCl-induced CTA. These findings support the notion that lithium has antagonistic actions on 5-HT1A receptors. Inhibition of 5-HT synthesis by PCPA failed, however, to prevent lithium-induced CTA. Evidently, mechanisms other than those governed solely by 5-HT are also involved in lithium-induced CTA.
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  • 92
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    Psychopharmacology 133 (1997), S. 383-388 
    ISSN: 1432-2072
    Keywords: Key words Intracranial self stimulation (ICSS) ; Dopamine ; Rat ; GABA transaminase inhibitor ; Vigabatrin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Gamma-vinyl GABA (GVG, also referred to as vigabatrin), an irreversible inhibitor of GABA transaminase (GABA-T), raises levels of GABA in nerve terminals, inhibits striatal dopamine release, and attenuates cocaine-induced increases in extracellular dopamine in the striatum and nucleus accumbens. In order to determine the action of GVG on dopamine-mediated reward, we examined its effects on the threshold for rewarding brain stimulation in male F-344 rats. GVG dose-dependently raised brain stimulation reward (BSR) thresholds at doses of 200, 300, and 400 mg/kg without significant effects on motor performance as measured by response latencies. In order to determine if GVG had similar modulatory effects on cocaine-induced lowering of BSR thresholds, the effective doses of GVG were co-administered with 2.5 and 5.0 mg/kg cocaine, doses that significantly lower BSR thresholds. The 400 mg/kg dose of GVG significantly blocked the lowering of thresholds seen at each dose of cocaine. Cocaine in combination with 200 or 300 mg/kg GVG, doses of GVG that significantly raise BSR thresholds, resulted in thresholds not significantly different from those obtained with cocaine alone. These data demonstrate that, at the doses tested, GVG is more effective at modulating basal reward thresholds than at modulating thresholds lowered by cocaine, implying that as dopaminergic activity increases, GABAergic activity must also increase in order to exert its inhibitory influence on dopaminergic activity.
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  • 93
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    Psychopharmacology 134 (1997), S. 319-329 
    ISSN: 1432-2072
    Keywords: Key words Animal model of depression Chronic mild stress ; Predictive validity ; Face validity Construct validity ; Reliability ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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  • 94
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Reinforcement ; Intravenous self-administration ; Strain differences ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Nicotine has been shown to maintain intravenous self-administration behaviour in humans and laboratory animals. However, factors critical in the initiation of nicotine self administration are not well defined. In particular genetic differences and effects of pre-exposure to nicotine have not been examined. Male Sprague-Dawley or Long-Evans rats were surgically prepared with indwelling jugular catheters and 3 days later received chronic injections of nicotine (0.4 mg/kg SC) or vehicle (saline, 1 ml/kg) for 7 days in their home cage. The next day, 2-h daily test sessions were initiated, during which rats were given the opportunity to nose-poke for nicotine infusions (0.015, 0.03 or 0.06 mg/kg per infusion) under a one-response fixed-ratio (FR-1) schedule of reinforcement with a 20-s time out after each infusion. One hole was defined as active while pokes in the other hole were recorded but had no scheduled consequence. The response requirement was increased progressively to five (FR-5) over successive sessions. Both saline- and nicotine-pretreated Sprague-Dawley rats showed a preference for the active hole, while only the saline-pretreated Long-Evans rats acquired the self-administration as defined by significant differences between responding in the active versus the inactive holes. The Fisher (F344) and Lewis inbred strains also failed to acquire self-administration of nicotine under these conditions. With Sprague-Dawley and Long-Evans rats that acquired the self-administration, and showed stable levels of maintained responding for nicotine, substituting saline for the nicotine or pretreating with mecamylamine (2.0 mg/kg SC) extinguished the behaviour. When dose per infusion was varied, an inverted U-shaped dose-response curve was obtained. These results support previous reports that nicotine can serve as a reinforcer in rodents and demonstrate that environmental factors such as prior nicotine exposure or genetic factors such as rat strain can affect acquisition of nicotine self-administration.
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  • 95
    ISSN: 1432-2072
    Keywords: Key words 5-Hydroxytryptamine ; 5 ; 7-Dihydroxytryptamine ; Operant behaviour ; Time discrimination ; Memory for duration ; Interval bisection procedure ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a ‘correct’ response, reinforcer delivery. When 〉 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered.
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  • 96
    ISSN: 1432-2072
    Keywords: Key words Sertraline ; Imipramine ; β-receptor ; 5-HT2 receptor ; 5-HT1A receptor ; Adenylate cyclase ; Water wheel test ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Effects of chronic treatment with selective 5-HT reuptake inhibitors (SSRIs) on the monoaminergic functions have not been much investigated in compared with tricyclic antidepressants. Therefore, we compared the effects of 3-week treatment with sertraline, a potent SSRI, to those of imipramine (10 mg/kg, IP, twice a day), on monoamine receptors and adenylate cyclase (AC) activity in rat brain. Two-week treatment with both sertraline and imipramine reduced immobility in the water wheel test to the comparable extent. Sertraline treatment did not affect Kd and Bmax of [3H]CGP12177 and [3H]ketanserin bindings or cAMP accumulation by norepinephrine, isoproterenol, 5’-guanylylimidodiphosphate [Gpp(NH)p] and forskolin in the cortical membrane compared with vehicle-treated rats. On the other hand, imipramine treatment decreased Bmax of both bindings and norepinephrine- or isoproterenol-stimulated cAMP accumulation. Treatment with either antidepressant induced no apparent changes in [3H]8-OH-DPAT [2-(N, N-dipropylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene] binding in the hippocampal membrane. These results suggested that chronic treatment of sertraline induced little effect on monoamine receptors and AC activity in the brain and that the alteration of these functions may not be primarily involved in antidepressive effects of antidepressants, at least of SSRIs.
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  • 97
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    Psychopharmacology 131 (1997), S. 23-33 
    ISSN: 1432-2072
    Keywords: Key words Social isolation ; Environmental enrichment ; Reward ; Rat ; Locomotor activity ; Sensitisation ; Conditioned reinforcement ; d-Amphetamine ; Cocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Post-weaning social isolation can induce profound and long lasting effects on an animal’s behaviour. The present study investigated the influence of post-weaning housing conditions on the sensitivity of rats to the behavioural effects of d-amphetamine and cocaine. The locomotor stimulant effects of both drugs were compared following acute and chronic administration. The influence of post-weaning housing conditions on the effects of d-amphetamine and cocaine on responding for food and for a conditioned reinforcer were also examined. Isolated rats showed enhanced locomotor activity on exposure to a novel environment. This difference was further exaggerated following administration of d-amphetamine (0.5 mg/kg) and cocaine (5 mg/kg). Isolated, but not enriched, rats exhibited sensitisation to the locomotor activating effects of repeated administration of a dose of 0.5 mg/kg d-amphetamine, whilst both groups sensitised equally to a dose of 1.0 mg/kg d-amphetamine. Rearing conditions did not affect sensitisation to cocaine (5, 10 mg/kg). Isolated rats exhibited a higher rate of responding for a conditioned stimulus and for food on a progressive ratio schedule of reinforcement, both of which were enhanced to a greater extent in isolates following administration of cocaine (5 mg/kg) and d-amphetamine (0.5 mg/kg). These results suggest that isolation rearing induces an enhancement in sensitivity to both the locomotor stimulant and reinforcing properties of amphetamine and cocaine.
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  • 98
    ISSN: 1432-2072
    Keywords: Key words Imipramine ; Serotonin ; Raphe nuclei ; Prefrontal cortex ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg SC), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg SC did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg SC imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55–65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60–70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg SC significantly increased 5-HT levels in both raphe nuclei (190 ± 20% above basal value) and prefrontal cortex (280 ± 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg SC), a non-selective 5-HT1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg SC) increased extracellular 5-HT in both raphe nuclei (155 ± 20% above basal value) and prefrontal cortex (160 ± 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine.
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  • 99
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    Urological research 25 (1997), S. 173-177 
    ISSN: 1434-0879
    Keywords: αB crystallin ; Heat shock protein ; Rat ; Kidney neoplasms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression of two small stress proteins, αB crystallin and the 27-kDa heat shock protein (HSP27), was studied quantitatively and immunohistochemically in normal kidney and renal tumors in rats. Levels of αB crystallin in renal cell tumors tended to be higher than in normal kidney (P = 0.07), but with a wide range of values, whereas they were significantly lower in mesenchymal tumors (P 〈 0.0001). In contrast, HSP27 concentrations in both renal cell (mean ± SD: 1790 ± 940 ng/mg protein,n = 15) and mesenchymal (1260 ± 1080 ng/mg protein,n = 10) tumors were significantly higher than the normal kidney value (142 ± 30 ng/mg protein,n = 10,P 〈 0.0001). A positive correlation was found between αB crystallin and HSP27 levels limited to the renal cell tumor case (Pearson's correlation coefficient,r = 0.68,P 〈 0.01). Immunohistochemistry revealed the loops of Henle to be positive for αB crystallin, whereas HSP27 staining was positive in glomerular and interstitial vascular walls and epithelial cells of proximal and distal tubules. Positive immunostaining for αB crystallin was demonstrated in six of nine renal cell tumors (67%) studied and for HSP27 in all of the nine cases (100%).
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  • 100
    ISSN: 1434-0879
    Keywords: Renal cell carcinoma ; Renal tubular transport ; Renal cortical slices ; p-Aminohippurate ; Human ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In vitro accumulation ofp-aminohippurate (PAH) was investigated in “intact” human renal cortical slices of normal kidney tissue and in tissue slices of renal cell carcinoma (RCC). The technique used was established in preliminary experiments on rat kidney tissue slices. In principle, the accumulation capacity is comparable in renal tissue slices of both species (slice to medium accumulation ratios between 4 and 8). In man sex differences in accumulation capacity do not exist. But, as shown in detail for rats, accumulation capacity drops with age. Tissue slices of RCC are unable to accumulate PAH actively; slice to medium ratio reaches about 1 and indicates passive PAH uptake only. Surprisingly, in tumors of stage pTl PAH uptake is lowest, perhaps as a sign of PAH transport out of the cells. There is no difference between peripheral and central parts of RCC. Age and sex are without influence on PAH uptake in RCC tissue slices. Interestingly, the accumulation capacity of “intact” tissue of kidneys infested with RCC also depends on the severity of the tumor (stage, diameter), but not on grading and formation of metastases.
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