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  • 101
    ISSN: 1432-1106
    Keywords: Hyperalgesia ; Peripheral neuropathy ; Nerve histopathology ; Neuropathic pain ; Unmyelinated fibre ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A mononeuropathy, produced by ligation of the sciatic nerve in rats, has recently been proposed as an animal model of experimental pain and pain-related disorders (hyperalgesia and allodynia). We investigated quantitatively the morphological changes in myelinated and unmyelinated fibres of the sciatic nerves 2 weeks after ligation in rats exhibiting allodynia to thermal stimulation. There was a marked reduction in the number of large myelinated fibres distal to the ligature (711 ± 34 compared with 5315 ± 230 in normal nerves). We also found a significant loss of small myelinated fibres (2429 ± 109 compared with 3197 ± 308 in normal nerves), the remaining fibres of this type showing pathological properties. Finally, ultrastructural evidence of damage to unmyelinated fibres was found. The typical pattern of large clusters of normal unmyelinated axons was no longer present within most regions of the nerve. There was a significant reduction in the size of the unmyelinated fibres (0.41 μm ± 0.15 compared with 0.71 μm ± 0.08 in normal nerves), together with a twofold increase in their number per cluster. Hypotheses about the mechanism of thermal allodynia in this pain model therefore must take into account the fact that all fibre classes show pathological changes.
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  • 102
    ISSN: 1432-1106
    Keywords: Transplantation ; Developmental neurobiology ; Retrograde labelling ; Immunocytochemistry ; Acetylcholinesterase histochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Embryonic spinal cord grafts from 12-day-old rat embryos were placed into the lumbar spinal cord of adult rats depleted of sciatic motoneurones by a neonatal nerve injury. A soleus muscle was removed from the leg and implanted paravertebrally, the proximal end of its nerve connected to the graft site. Fluorescent retrograde tracers injected into the soleus implant, 37–64 days postoperatively, labelled neurones that had grown axons to the muscle. Approximately one-fifth of retrogradely labelled neurones were within the graft; however, the majority were found within the host spinal cord close to the graft. These included large neurones within the motoneurone-depleted dorsolateral ventral horn. In control experiments a muscle and nerve were implanted but no embryonic tissue grafted. Significantly fewer neurones were labelled. In some animals, one tracer was injected into the soleus muscle whilst another was applied to the cut sciatic nerve ipsilateral to the graft site. No neurones were found to project axons to both targets. In animals that received grafts prelabelled with bromodeoxyuridine (BrDU) some neurones were found to be both BrDU positive and retrogradely labelled from the soleus implant. These were most frequently within the motoneuronedepleted ventral horn ipsilateral to the graft. Thus, grafted neurones may migrate to an appropriate location within the host neuropil. Acetylcholinesterase (AChE) histochemistry showed the graft site contained immature but AChE-positive neurones. Some regions of host ventral horn contained unusually few AChE-positive nerve fibres and occasional large AChE-positive neurones, some of which were also retrogradely labelled from the implanted muscle. Studies of implanted soleus 21–90 days after transplantation showed that muscle fibres, after initial degeneration, regenerated displaying differing phenotypes, presumably under the influence of new motor innervation.
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  • 103
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 91 (1992), S. 415-424 
    ISSN: 1432-1106
    Keywords: Taste ; Insular cortex ; Response profile ; Inhibitory response ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The responses of 84 taste neurons to stimulation of the oral cavity in rats were examined; most taste neurons were found in either a granular insular area (area GI; n = 55) or dysgranular insular area (DI; n = 25), and the others (n = 4) were in an agranular insular area (area AI). The fraction of neurons responding to only one of the four basic stimuli was significantly larger in area GI than in area DI. When neurons were classified by the stimulus which most excited the neuron among the four basic stimuli, every “best-stimulus category” of neurons was found in both GI and DI areas. Quinine-best and “multistimulus-type” neurons, whose responses to some non-best stimulus exceeded 90% of the maximum, were more numerous in the cortex than in the thalamocortical relay neurons. When responses were plotted against taste stimuli arranged in the order of sucrose, NaCl, HCl, and quinine along the abscissa (taste coordinate), response profiles of taste neurons often showed two peaks. The double-peaked type of response profiles were found in every best-stimulus category of neurons in both areas; though, a significantly large fraction of quinine-best neurons in area GI were of the double-peaked type. Some taste neurons in area GI (n = 21) and in area DI (n = 7) were inhibited by one to two taste stimuli, particularly by the stimuli present next to the best one along the taste coordinate. In correlation profiles — correlation coefficients between sucrose and NaCl and between HCl and quinine — pairs of stimuli which were located next to each other on the taste coordinate were significantly smaller in area GI than in area DI. It is thus highly probable that area GI plays an important role in fine taste discrimination and area DI in integration of taste information.
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  • 104
    ISSN: 1432-1106
    Keywords: Cervical ; Cuneate ; Trigeminal ; Primary afferents ; Somatosensory ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were performed on rats to determine whether primary afferents from the upper cervical region terminate directly on Spinothalamic and propriospinal neurones. The central terminations of primary afferents from the upper cervical region were identified by diffusely filling their axons with horseradish peroxidase. Spinothalamic neurones or propriospinal neurones were identified in the same experimental animals by using retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase. Approximately 3–11 % of Spinothalamic cells in laminae 4–6 of spinal segments C2–4 received apparent synaptic contacts from primary afferents on the soma or primary dendrites. Approximately 18–36% of propriospinal neurones with axons descending to lower thoracic or lumbar levels received apparent synaptic contacts on the soma or primary dendrites. These data provide anatomical evidence that Spinothalamic and long propriospinal neurones in the upper cervical cord are excited directly by primary afferents. The data also help to clarify the neural circuitry underlying somatic sensation and reflex movements evoked by neck receptors.
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  • 105
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 88 (1992), S. 33-40 
    ISSN: 1432-1106
    Keywords: Corpus callosum ; Frontal agranular cortex ; GABA receptor ; NMDA receptor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A slice preparation of rat frontal agranular cortex preserving commissural inputs has been used for intracellular recording from layer V pyramidal cells, in order to characterize the synaptic potentials induced by stimulation of the corpus callosum and to reveal the subtypes of amino acid receptors involved. Stimulation of the corpus callosum induced EPSPs followed by early IPSPs with a peak latency of 30 ± 2 ms and late IPSPs with a peak latency of 185 ± 18 ms. Reversal potentials for early and late IPSPs were −75 ± 5 mV (early) and −96 ± 5 mV (late). Late IPSPs were more dependent on extracellular K+ concentration. The early IPSPs were blocked by GABAA antagonists, bicuculline and picrotoxin, whereas the late IPSPs were reduced by the GABAB antagonist, phaclofen. CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), an antagonist of non-NMDA (N-methyl-D-aspartate) receptors, suppressed both EPSPs and late IPSPs at 5 µM. Early IPSPs remained at this concentration but were suppressed by 20 µM CNQX. In Mg2+-free solution, EPSPs were larger and more prolonged than in control solution. These enhanced EPSPs persisted after 5 to 20 µM CNQX, but were reduced in amplitude, and their onset was delayed by 3.6 ± 0.8 ms. The remaining EPSPs were suppressed by 50 µM APV (DL-2-amino-5-phosphono-valeric acid), an antagonist of NMDA receptors. In Mg2+-free solution containing 5 to 20 µM CNQX, the late IPSPs were not diminished. The remaining late IPSPs were suppressed by APV or by phaclofen. By contrast, the amplitude of early IPSPs was not affected by APV in Mg2+-free solution containing 5 µM CNQX. These results show that stimulation of the corpus callosum can induce GABAA and GABAB dependent IPSPs and NMDA and non-NMDA dependent excitation. It is suggested that these four types of amino acid-based transmission are conveyed by intracortical pathways with different characteristics.
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  • 106
    ISSN: 1432-1106
    Keywords: Cerebral ischemia ; Glutamate ; Heat shock protein ; Hippocampus ; Programmed cell death ; Rat ; Ubiquitin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructural changes in the pyramidal neurons of the CA1 region of the hippocampus were studied 6 h, 24 h, 48 h, and 72 h following a transient 10 min period of cerebral ischemia induced by common carotid occlusion combined with hypotension. The pyramidal neurons showed delayed neuronal death (DND), i.e. at 24 h and 48 h postischemia few structural alterations were noted in the light microscope, while at 72 h extensive neuronal degeneration was apparent. The most prominent early ultrastructural changes were polysome disaggregation, and the appearance of electron-dense fluffy dark material associated with tubular saccules. Mitochondria and nuclear elements appeared intact until frank neuronal degeneration. The dark material accumulated with extended periods of recirculation in soma and in the main trunks of proximal dendrites, often beneath the plasma membrane, less frequently in the distal dendrites and seldom in spines. Protein synthesis inhibitors (anisomycin, cycloheximide) and an RNA synthesis inhibitor (actinomycin D), administered by intrahippocampal injections or subcutanously, did not mitigate neuronal damage. Therefore, DND is probably not apoptosis or a form of programmed cell death. We propose that the dark material accumulating in the postischemic period represents protein complexes, possibly aggregates of proteins or internalized plasma membrane fragments, which may disrupt vital cellular structure and functions, leading to cell death.
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  • 107
    ISSN: 1432-1106
    Keywords: 6-OHDA lesion ; Foetal ventral mesencephalic graft ; L-DOPA and carbidopa ; Parkinson's disease ; Circling behaviour ; Neural grafting ; Gliosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway, foetal ventral mesencephalic grafts implanted into the 6-OHDA-lesioned striatum produced a reduction in apomorphine-induced contralateral rotation, and complete abolition of (+)-amphetamine-induced ipsilateral rotation. The graft-induced reduction of apomorphine and (+)-amphetamine-induced rotation was not affected by chronic 27 week administration of L-DOPA and carbidopa to rats receiving foetal grafts. TH-immunohistochemistry revealed 〉96% loss of dopamine cells in the substantia nigra ipsilateral to the 6-OHDA lesion in all animals, but cell loss in the ipsilateral ventral tegmental area was more variable (21–46% of the intact side). TH-positive cells in the intact substantia nigra and ventral tegmental area were not affected by chronic treatment with L-DOPA and carbidopa. In the lesioned striatum of rats receiving sham grafts, no TH-positive cells or fibres were seen. In the 6-OHDA-lesioned striatum of animals receiving foetal grafts, many TH-positive cells were seen in the grafts and chronic treatment with L-DOPA and carbidopa did not reduce cell survival. GFA-P immunohistochemistry revealed that a unilateral 6-OHDA lesion followed by a sham graft was not associated with a reactive gliosis reaction in the striatum at the time of study (38 weeks after lesion surgery and 30 weeks after sham-graft), and treatment of such rats with L-DOPA and carbidopa was also without effect on glia. In contrast there was a marked gliosis in the striatum surrounding foetal grafts which was unaffected by chronic treatment with L-DOPA and carbidopa. The grafts themselves were surrounded by a rim of glial cells, and the glial density within the grafts was higher in animals receiving chronic L-DOPA and carbidopa treatment. However, there was no obvious relationship between the number of TH-positive cells within the grafts, or graft volume, and glial cell density within the grafts. These results suggest that long-term treatment with L-DOPA and carbidopa does not impair either the behavioural recovery produced by foetal ventral mesencephalic grafts in rats or the long-term survival of grafts as revealed by TH-immunohistochemistry. The presence of a foetal graft is associated with a reactive gliosis in the implanted striatum, which was not altered by long-term treatment with L-DOPA and carbidopa. However such treatment did result in an increase in glial density within the grafts themselves.
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  • 108
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 88 (1992), S. 451-454 
    ISSN: 1432-1106
    Keywords: Subparafascicular area ; Amygdala ; Striatum ; Fluorescent tracer ; Tyrosine hydroxylase immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The dopaminergic nature of the pathway from the subparafascicular thalamic nucleus and its adjacent region to the amygdala was reexamined by means of retrograde fluorescent tracers coupled with tyrosine hydroxylase (TH) immunofluorescence. After injecting a small amount of tracer into the amygdala, retrogradely labeled cells were found in the subparafascicular thalamic nucleus and its adjacent periventricular region. TH immunofluorescence showed that these labeled cells completely lacked TH immunoreactivity. Similar results were obtained when a larger amount of tracer was applied to the amygdala. The present study, in contrast to the previous report describing the dopaminergic innervation of the amygdala by the cells in and around the subparafascicular area (A11 catecholamine cell group), indicates that the A11 cell group does not contribute to a dopaminergic input to the amygdala.
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  • 109
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 88 (1992), S. 485-494 
    ISSN: 1432-1106
    Keywords: Glutamate ; Hippocampal pyramidal cells ; Action potentials ; Prepotentials ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary (1) The responses of CA1 pyramidal cells to short glutamate pulses (10–50 ms) delivered at sensitive spots in the apical dendrites have been analysed by intracellular recording. (2) The glutamate pulses elicited stable depolarizing responses in a dose- and frequencydependent manner. (3) When a single action potential with a firing probability around 0.5 was elicited, a subtraction procedure showed that a slow depolarizing ramp preceded each spike. We call this ramp the glutamate-induced prepotential (GluPP). (4) In contrast to the upward convex subthreshold depolarization the GluPP was upward concave. (5) The GluPP amplitude and time course increased with depolarization of the membrane, a phenomenon which appears to be connected to the elevation of action potential threshold. (6) The GluPP was regenerative since once started, it ended in an action potential. (7) A specific N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonovaleric acid (50 μM) reduced the glutamateinduced depolarization, but did not affect the form or amplitude of GluPP, once the latter was induced. (8) It is concluded that short glutamate pulses elicited action potentials through a prepotential mechanism, similar to the slow prepotentials induced by long depolarizing current pulses across the soma membrane. (9) A possible physiological role for the GluPP is discussed.
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  • 110
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 88 (1992), S. 473-484 
    ISSN: 1432-1106
    Keywords: Cervical ; Cuneate ; Trigeminal ; Primary afferents ; Somatosensory ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were performed on rats to determine the location of thalamic projecting neurones in the medulla which receive direct contacts from neck primary afferents. The medullary terminations of primary afferents from the cervical region were identified by silver staining their degenerating terminals, diffusely filling their axons with horseradish peroxidase (HRP), or reacting for transganglionically transported HRP applied to muscle or cutaneous nerves. Neurones projecting to the ventrobasal thalamus were identified in the same experimental animals by using retrograde transport of HRP or Fluoro-Gold. En passant swellings or terminals of neck primary afferents were found in the vicinity of neurones projecting to the thalamus in the dorsolateral part of the rostral cuneate nucleus, the ventral aspect of the external cuneate nucleus, and the border zone between the two. Terminals of neck afferents and retrogradely labelled cells also coincided in nucleus x. Putative synaptic contacts were found in the region between the dorsolateral part of the rostral cuneate nucleus and ventromedial external cuneate nucleus. Cutaneous afferents from the neck were associated with thalamic projecting cells located along the dorsolateral border of the rostral cuneate nucleus, and afferents from neck muscles were associated with thalamic projecting cells in the caudal third of the external cuneate nucleus and in nucleus x.
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  • 111
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 88 (1992), S. 517-530 
    ISSN: 1432-1106
    Keywords: Basal ganglia ; Globus pallidus ; Neostriatum ; Movement Neuronal activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Single-unit extracellular neuronal recordings were obtained from the globus pallidus (GP) and the neostriatum (NS) of rats while they performed a learned head movement in response to an auditory cue. In both GP and NS, units that altered their discharge rate in association with head movements and with the cues that triggered these head movements were prevalent. Frequently, the responses were directionally-specific (i.e., the magnitude or direction of change in firing rate of these neurons was substantially different for trials in which head movements were made to the left vs. the right). For some units, firing rates were altered only in response to the movement cue or only in association with head movements. However, the majority of neurons exhibited responses with both cue-related and movement-related components. Neuronal responses to the auditory cue usually were context-dependent, in that they did not occur if the same stimulus was presented when the animal was not performing the task. At least a small proportion of GP and NS neurons also appeared to exhibit context-dependent movement-related activity, in that responses occasionally were observed that were associated either with sensory-triggered head movements or with spontaneous head movements, but not with both. These data are consistent with previous suggestions that the activity of basal ganglia neurons during movement performance is highly dependent on the conditions associated with movement initiation. The data also indicate that the response characteristics of both GP and NS neurons in the rat are generally similar to those that have been described for basal ganglia neurons in primates and cats during sensory triggered movement tasks. However, the proportion of task-related neurons that exhibited responses with both movement-related and cue-related components was greater than has generally been reported in studies of cats and primates, suggesting that neurons with these response properties may be more predominant in the rat basal ganglia.
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  • 112
    ISSN: 1432-1106
    Keywords: Glutamate ; GABA ; Immunocytochemistry ; Pontine nuclei ; Transmitter release ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A quantitative electron microscopic immunocytochemical method was used to study the synaptic handling of glutamate and GABA in slice preparations from the rat pontine nuclei. Slices were subjected to a depolarizing stimulus (55 mM K+, 20 min) in the presence of a physiological or low Ca2+concentration. Depolarization at physiological [Ca2+] evoked a depletion of glutamate-like immunoreactivity from nerve terminals that contain round vesicles and establish asymmetric synaptic contacts. When depolarization was induced in the presence of only 0.1 mM Ca2+ (10 mM Mg2+ added), the loss of glutamate was significantly reduced or abolished, indicative of a Ca2+dependent component of glutamate release. By means of a double labeling immunocytochemical method we could identify a population of nerve terminals that displayed strong GABA-like immunoreactivity, and a level of glutamate like immunoreactivity that was low but yet clearly above background level. This type of terminal contains elongated or pleomorphic vesicles and establishes symmetric synaptic contacts. In these terminals, depolarization evoked a Ca2+-dependent depletion of GABA like immunoreactivity, but failed to change the level of glutamate like immunoreactivity. The present study demonstrates that two different types of nerve terminal in the rat pontine nuclei contain releasable pools of glutamate and GABA, respectively, and that the GABA releasing terminals also contain a non releasable pool of glutamate. The glutamate of the latter pool could act as precursor of GABA.
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  • 113
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 89 (1992), S. 581-587 
    ISSN: 1432-1106
    Keywords: Norepinephrine ; Hippocampus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glutamate pressure ejections in the vicinity of locus coeruleus (LC) neurons have been shown to produce both short and long-lasting potentiation of perforant path (PP) evoked population spike amplitude in the dentate gyrus (DG). These effects of LC-glutamate activation resemble those produced by direct application of NE in vitro or in vivo. The present study monitored the cellular response of LC neurons to local glutamate ejections concomitant with stimulation of the PP evoked potential. Double barrel micropipettes or 33 ga cannulaelectrode assemblies permitted LC unit recording and glutamate ejection at or near the same site in urethane anesthetized rats. Glutamate ejections produced a burst of LC activity lasting 250–400 ms and followed by a depression of unit activity lasting 4.6 min. The maximal spike potentiation produced by LC activation was 158%. The first spike to exceed the control range occurred 34 s after the LC burst. Comparable silent intervals in LC unit activity induced by systemic clonidine were not accompanied by population spike amplitude potentiation. The mean duration of potentiation was 4.4 min except in four cases where responses remained potentiated for the duration of the experiment. The duration of potentiation was not correlated with the termination of LC depression. LC units recovered to baseline rates following glutamate induced depression of activity. The occurrence of potentiation appeared to require that glutamate activation reach a critical number of LC neurons since small glutamate ejections could produce a local burst without eliciting potentiation. Long-lasting changes were also related to larger glutamate volumes (100 nl). EPSP slope increases were briefer and occurred less frequently than spike amplitude changes suggesting EPSP-spike dissociation. The delay between the burst of LC activity and amplitude increases in the DG supports a model of NE action in which there are both rapid and slowly developing effects of NE release in the DG. In summary, brief, but intense, activation of LC neurons produces a delayed potentiation of DG responses lasting minutes to hours following the LC burst.
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  • 114
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 90 (1992), S. 47-53 
    ISSN: 1432-1106
    Keywords: Energy metabolism ; Free nucleotides ; Ischemia ; Brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Loss of cellular ion homeostasis during anoxia, with rapid downhill fluxes of K+, Ca2+, Na+ and Cl-, is preceded by a slow rise in extracellular K+ concentration (K e + ), probably reflecting early activation of a K+ conductance. It has been proposed that this conductance is activated by either a rise in intracellular calcium concentration (Ca i 2+ ), or by a fall in ATP concentration. In a previous study from this laboratory (Folbergrová et al. 1990) we explored whether the early activation of a K+ conductance could be triggered by a rise in Ca i 2+ . To that end, labile metabolites and phosphorylase a, a calcium sensitive enzyme, were measured after 15, 30, 60 and 120 s of complete ischemia (“anoxia”). In the present study, we investigated whether brief anoxia is accompanied by changes in ATP/ADP ratio, or in the phosphate potential, which could cause activation of a K+ conductance. To provide information on this issue, we added a group with 45 s of anoxia to the previously reported groups, and derived changes in intracellular pH (pHi). This allowed calculations of the free concentrations of ADP (ADPf) and AMP (AMPf) from the creatine kinase and adenylate kinase equilibria, and hence the derivation of ATP/ADPf ratios. In performing these calculations we initially assumed that the free intracellular Mg2+ concentration remained unchanged at 1 mM. However we also explored how a change in Mg i 2+ of the type described by Brooks and Bachelard (1989) influenced the calculation. The results showed that ADPf must have risen to 150–200% of control within 15 s, and to 330–350% of control within 45 s of anoxia. The concentration of AMPf should have increased 2–4 fold in 15 s and 10–20 fold in 45 s. Thus although tissue ATP concentration usually remains 〉90% of control within the first 30s of anoxia, and 〉80% of control within the first 45 s, the ATP/ADPf ratios change markedly at a time when alterations in ion homeostasis are dominated by a moderate rise in K e + , and long before massive ion fluxes occur and the cells depolarise (after about 60–70 s). Such early changes in ATP/ADPf ratio, or in phosphate potential, could well influence reactions which are coupled to ATP hydrolysis, and perhaps lead to activation of ATP-dependent K+ conductances.
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  • 115
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    Experimental brain research 90 (1992), S. 29-39 
    ISSN: 1432-1106
    Keywords: Direct Cortical Response ; Sensory Evoked ; Response ; Current Source Density ; Somatosensory Cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A current-flow and current-source-density analysis of the sensory evoked response (SER) and the direct cortical response (DCR) in the somatosensory cortex of rats was performed to determine the origin of these potentials. The SER was found to originate in layers II and III, as in cats, with a single excitatory neuronal circuit component. The DCR, on the other hand, has five components, three inhibitory and two excitatory. The activation and magnitude of these components vary with stimulus strength and frequency. During the second and fourth ms of the response, two inhibitory currents flow in layers V and VI; 2 ms later, excitatory current flows in layers II and III. This excitatory current appears to be the same one involved in the SER. Five ms later, the superficial excitatory current is replaced by an inhibitory one in the neighborhood of the DCR's negative peak. At strong stimulus strengths, this is followed by an excitatory current in layer V. The early inhibitory and excitatory components step up through layers upper-VI, V and III over time, implying that inhibition followed by excitation moves upward through cortex. The currents associated with the DCR in somatosensory cortex are compared with those for the DCR in motor and association cortex.
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  • 116
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    Electronic Resource
    Springer
    Experimental brain research 90 (1992), S. 343-345 
    ISSN: 1432-1106
    Keywords: Motoneuron ; Motor axon ; Nerve conduction ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Axon conduction distance, conduction velocity, and conduction time were measured for individual triceps surae motoneurons in Sprague-Dawley rats weighing 230–630 g (i.e., age range 6–16 weeks). Both conduction distance (nerve length) and velocity were closely correlated with weight (r=0.95 and r=0.82, respectively). In contrast, conduction time did not change as weight increased nearly threefold. This striking constancy is probably due to a corresponding increase in axon diameter. It could contribute to maintenance of stable motor performance during rapid growth.
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  • 117
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    Experimental brain research 90 (1992), S. 508-518 
    ISSN: 1432-1106
    Keywords: Subparafascicular nucleus ; Inferior colliculus ; Superior olivary complex ; Cochlear nuclei ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the course of our study on the neuronal connections of the subparafascicular nucleus (SPF) in the rat, descending projections from the SPF to the lower brain stem were examined by using the anterograde tracer PHA-L (Phaseolus vulgaris leukoagglutinin) and retrograde tracer WGA-HRP (horseradish peroxidase conjugated to wheat germ agglutinin). When PHA-L was injected into the magnocellular and/or parvicellular division of the SPF (SPFm and/or SPFp), presumed terminal labeling was seen, bilaterally with an ipsilateral dominance, in the mesencephalic and pontine central gray matter, peripheral shell regions of the inferior colliculus, cuneiform nucleus, and superior olivary complex (mainly in the superior paraolivary nucleus, and additionally in the nuclei of the trapezoid body). A few labeled axon terminals were also seen in the cochlear nuclei bilaterally with a contralateral dominance. In the second set of experiments, WGA-HRP was injected into the inferior colliculus, superior olivary complex, or cochlear nuclei. When WGA-HRP was injected into the peripheral shell regions of the inferior colliculus or the superior olivary complex, many labeled neuronal cell bodies were seen in the SPFm bilaterally with an ipsilateral dominance, and a moderate number of labeled neuronal cell bodies were observed in the SPFp (lateral SPF) bilaterally with an ipsilateral dominance. When WGA-HRP was injected into the cochlear nuclei, a moderate number of labeled neuronal cell bodies were observed in the SPFm and SPFp bilaterally with a contralateral dominance. The results indicate that the SPFm and SPFp (lateral SPF) of the rat send a considerable number of projection fibers to the lower brain stem. The target regions of these projection fibers include the auditory relay nuclei, such as the inferior colliculus, superior olivary complex, and cochlear nuclei.
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  • 118
    ISSN: 1432-1106
    Keywords: Medial vestibular nuclei ; Potentiation ; Depression ; AP5 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.
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  • 119
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    Experimental brain research 90 (1992), S. 567-571 
    ISSN: 1432-1106
    Keywords: Mesencephalic trigeminal neurons ; Peripheral nerve transection ; Cell loss ; Transganglionic degeneration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of peripheral nerve transection on mesencephalic trigeminal (MeV) neurons have been studied qualitatively and quantitatively in the rat. In the qualitative part of the study the brain stem was studied in Fink-Heimer stained sections 3–30 days after a masseteric nerve transection. Degeneration argyrophilia was observed both in the MeV tract and in the supratrigeminal and trigeminal motor nuclei, as well as in the lateral part of the brain stem reticular formation. The first signs of transganglionic degeneration (TGD) were seen 7 days postoperatively, and the amount of degeneration increased considerably with longer survival times. A quantitative analysis of the MeV nucleus was made 60 days after transection of the left masseteric nerve. This analysis showed a 10.5–22.7% reduction of cells on the side that had undergone masseteric nerve transection. The mean difference (left vs right side) was -2.4% in animals that had not been operated on. These findings show that mesencephalic trigeminal neurons with proprioceptive functions are very sensitive to peripheral nerve injury with a substantial cell loss and TGD as the result.
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  • 120
    ISSN: 1432-1106
    Keywords: Intermediolateral cell column ; Degeneration ; Serotonergic projections ; Thyrotropin-releasing hormone ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study, we investigated the effects of the neonatal removal of the right superior cervical ganglion on the serotonin-like and thyrotropin-releasing-hormone-like immunoreactivities (5-HT-LI and TRH-LI) in the intermediolateral cell column (IML) of the spinal cord by quantitative image analysis. Two weeks after the lesion, we observed a 60% reduction in 5-HT-LI, while TRH-LI was not significantly reduced, in the right IML (lesioned side) at T1-2 levels. One month after the lesion, 5-HT-LI and TRH-LI were significantly reduced by 60% in the right IML at T1-2 levels. After 3 months, this decrease persisted at this level. In addition, we observed a 30% loss of the 5-HT-LI in the right IML at T3-4 levels, whereas TRH-LI did not decrease significantly at T3-4 levels. These findings are discussed and compared with those of other experimental studies on serotonergic reorganization in the rat spinal cord.
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  • 121
    ISSN: 1432-1106
    Keywords: Peripheral nerve injury ; Glabrous skin ; Sensory nerve endings ; Neuropeptide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunohistochemistry has been used to study, the capacity of different types of sensory axons in the saphenous nerve to extend into denervated glabrous skin territory after a chronic sciatic nerve lesion. In this study, the extension of the intact or regenerating thin peptidergic and coarse saphenous nerve fibres in adult and neonatal rats was determined. Substance P (SP) and calcitonin gene-related peptide (CGRP) antibodies were used as markers for thin axons and neurofilament (NF) antibodies for coarse axons. In addition, S-100 protein (S-100) antibodies, which primarily stain Schwann cells associated with myelinated axons, as well as innervated lamellated cells of Meissner corpuscles, were used. After a chronic sciatic nerve lesion in adult rats, thin dermal and epidermal SP-immunoreactive (IR) and CGRP-IR saphenous nerve fibres were present in an area lateral to that normally innervated by the saphenous nerve in the foot sole. In neonatally lesioned animals, thin dermal and epidermal SP-IR and CGRP-IR, as well as coarse dermal NF-IR fibres and S-100-IR cells, all of which derived from the saphenous nerve, were found in the sciatic nerve territory. In addition, some dermal SP-IR and CGRP-IR fibres were transiently present in the lateral part of the foot sole. After chronic sciatic nerve lesion and a concomitant crush injury of the saphenous nerve in adults or neonatals, thin dermal and epidermal SP-IR and CGRP-IR fibres, as well as coarse dermal NF-IR fibres and S-100-IR cells, were found in the innervation area normally occupied by the sciatic nerve. After a sciatic nerve cut and a concomitant crush injury of the saphenous nerve in adult rats, the SP-IR and CGRP-IR fibres, as well as the NF-IR fibres and S-100-IR cells were restricted to the medial part of this area. After a sciatic nerve cut and a concomitant crush injury of the saphenous nerve in neonatal rats, a few thin dermal SP-IR and CGRP-IR fibres were found in the lateral part of the foot sole as well. The findings of the present study together with those of previous morphological studies indicate that intact thin axons from the saphenous nerve, including those exhibiting peptide immunoreactivity, but not coarse saphenous axons, are capable of extending into “foreign” denervated glabrous skin after chronic sciatic nerve injuries. In neonatally sciatic-nerve-injured animals, both groups of axons spread from the intact saphenous nerve into the sciatic nerve territory. This was also the case when the saphenous nerve had been crushed and allowed to regenerate in rats injured neonatally, or as adults. However, judging from previous physiological data, the regenerating axons do not develop into functional low-threshold mechanoreceptors.
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  • 122
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    Experimental brain research 91 (1992), S. 94-104 
    ISSN: 1432-1106
    Keywords: Frequency modulation ; Intracellular recordings ; Horseradish peroxidase ; Inferior colliculus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The response characteristics to linear frequency sweeps were studied in two groups of FM (frequency modulation) sensitive neurons in the rat inferior colliculus. ‘FM specialized’ cells responded to frequency sweeps but not to pure tones. ‘Mixed’ cells responded to both frequency sweeps and pure tones. FM specialized cells preferred faster and broader sweeps of higher intensity than did mixed cells and were more directionally selective. In addition, FM specialized cells were more sharply tuned to FM velocity and FM range and had longer response latencies. Physiologically identified FM cells stained intracellularly with horseradish peroxidase revealed differences in morphology correlating with the differences in their responses to tones. FM specialized cells had larger dendritic fields, more dendritic branching and more dendritic spines than did mixed cells. The findings are taken as evidence that the two groups of inferior colliculus neurons are both functionally and morphologically distinct.
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  • 123
    ISSN: 1432-1106
    Keywords: Dopamine-rich transplants ; Fos protein ; Nigrostriatal system ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of the present experiment was to characterize the effect of intrastriatal grafts of embryonic dopaminergic neurones on the expression of Fos protein in the striatum when challenged with amphetamine. Unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were made in adult rats and grafting was performed 3 weeks later. The numbers of Fos-positive nuclei in the ipsi- and contralateral striata were counted on coronal sections following immunohistochemical staining 5 months after grafting. Administration of d-amphetamine induced an increase in the density of Fospositive nuclei in the intact striatum. This stimulatory effect of amphetamine on c-fos expression was blocked by 6-hydroxydopamine hydrobromide lesions and was restored in the striata bearing transplants. However, an overshoot was observed as the density of Fos-positive cells within the grafted striatum was larger than that observed within the intact striatum. This hyperexpression of Fos-positive nuclei was correlated with the exaggerated compensation of amphetamine-induced rotation in the same animals.
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  • 124
    ISSN: 1432-1106
    Keywords: GAP-43 ; In situ hybridization ; Spinal cord ; Axotomy ; Rat ; Cat ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In situ hybridization histochemistry was used to detect cell bodies expressing mRNA encoding for the phosphoprotein GAP-43 in the lumbosacral spinal cord of the adult rat, cat and monkey under normal conditions and, in the cat and rat, also after different types of lesions. In the normal spinal cord, a large number of neurons throughout the spinal cord gray matter were found to express GAP-43 mRNA. All neurons, both large and small, in the motor nucleus (Rexed's lamina IX) appeared labeled, indicating that both alpha and gamma motoneurons express GAP-43 mRNA under normal conditions. After axotomy by an incision in the ventral funiculus or a transection of ventral roots or peripheral nerves, GAP-43 mRNA was clearly upregulated in axotomized motoneurons, including both alpha and gamma motoneurons. An increase in GAP-43 mRNA expression was already detectable 24 h postoperatively in lumbar motoneurons both after a transection of the sciatic nerve at knee level and after a transection of ventral roots. At this time, a stronger response was seen in the motoneurons which had been subjected to the distal sciatic nerve transection than was apparent for the more proximal ventral root lesion. An upregulation of GAP-43 mRNA could also be found in intact motoneurons located on the side contralateral to the lesion, but only after a peripheral nerve transection, indicating that the concomitant influence of dorsal root afferents may play a role in GAP-43 mRNA regulation. However, a dorsal root transection alone did not seem to have any detectable influence on the expression of GAP-43 mRNA in spinal motoneurons, while the neurons located in the superficial laminae of the dorsal horn responded with an upregulation of GAP-43 mRNA. The presence of high levels of GAP-43 in neurons has been correlated with periods of axonal growth during both development and regeneration. The role for GAP-43 in neurons under normal conditions is not clear, but it may be linked with events underlying remodelling of synaptic relationships or transmitter release. Our findings provide an anatomical substrate to support such a hypothesis in the normal spinal cord, and indicate a potential role for GAP-43 in axon regeneration of the motoneurons, since GAP-43 mRNA levels was strongly upregulated following both peripheral axotomy and axotomy within the spinal cord. The upregulation of GAP-43 mRNA found in contralateral, presumably uninjured motoneurons after peripheral nerve transection, as well as in dorsal horn neurons after a dorsal root transection, indicates that GAP-43 levels are altered not only as a direct consequence of a lesion, but also after changes in the synaptic input to the neurons.
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  • 125
    ISSN: 1432-1106
    Keywords: Somatosensory cortex ; Pain-related behaviour ; Mononeuropathy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Single-unit recordings were made under moderate gaseous anaesthesia in the hindpaw representation area of the two primary somatosensory motor cortices (SmI) of rats (n = 58) rendered mononeuropathic by four loose ligatures placed around one common sciatic nerve 2–3 weeks beforehand. The rats exhibited clear hyperalgesia and allodynia from the paw with the ligated sciatic nerve, to both mechanical and thermal stimuli. From the tested neuronal population (n = 640), about the same proportion could be activated by somatic stimuli in each cortex: 165/362 (45%) in the cortex contralateral to the ligated sciatic nerve (Cc), 105/278 (37%) in the cortex ipsilateral to the ligated sciatic nerve (Ci). Neurones driven by light touch, exhibited RFs strictly contralateral to the recording sites. Their proportion and response characteristics were similar regardless of recording side. However, the number of neurones with RFs in the sciatic nerve territory was above 95% in the Ci, and was dramatically reduced to 43 % in the Cc. By contrast, the number of neurones with RFs supplied by the saphenous nerve reached 57% on this side. Although the RF size of all the neurones appeared roughly normal, there were fewer Cc than Ci neurones with RFs located on the paw itself and with RFs of extremely small size in the sciatic nerve territory. The proportion of neurones responding to a joint stimulus was significantly higher in the Cc than in the Ci. The neuronal responses to joint stimuli of the paw with the ligated sciatic nerve were significantly more sustained than those recorded in the Ci and elicited from the normal paw. The proportion of neurones driven by mechanical stimulation which gave rise to nociceptive reactions in freely moving animals, i.e. “nociceptive” neurones, was comparable in each cortex. However, half of the Cc neurones exhibited paroxysmal discharges occuring without intentional stimulation and of long duration (l min to several minutes). Only 66% of Cc but 93% of Ci “nociceptive” neurones were exclusively activated by pinch. The remaining Cc neurones were also activated by applying moderate pressure to the paw with the ligated nerve. Pinch responses from the paw with the ligated nerve were often more intense and of longer duration than responses elicited from the intact paw. The “nociceptive” Cc neurones were especially sensitive to thermal stimuli of 39–44° C when the stimuli were applied to the paw with the ligated nerve. They also responded vigorously to a 10° C stimulus applied to this paw. They were therefore, sensitive to thermal stimuli usually considered to be in the non-noxious range. In the SmI cortex opposite to the ligated sciatic nerve, there was no change in the proportion of somatosensory neurones, but a rearrangement of the various somatic inputs. Although reduced, there were consistent light tactile inputs from the damaged sciatic nerve giving rise to roughly normal neuronal responses, and simultaneously a noticeable increase in tactile signals from the saphenous nerve territory. There was also a significant increase in joint inputs from the paw with the ligated sciatic nerve. The possible functional role of such input rearrangement is discussed. The dramatic changes in the responses of “nociceptive” neurones to stimuli applied to the paw with the ligated sciatic nerve and the clear decrease in their activation threshold to mechanical and thermal stimuli could account for some of the abnormal pain-related behaviours that were exhibited. These data emphasize, again, that the primary sensory cortex is involved in nociceptive processing.
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  • 126
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    Experimental brain research 92 (1992), S. 46-58 
    ISSN: 1432-1106
    Keywords: Medullary reticular formation ; Gigantocellular reticular nucleus ; Reticulospinal ; Lateral and medial longissimus ; Lumbar and cervical spinal cord ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary These experiments tested hypotheses about the logic of reticulospinal and reticuloreticular controls over deep back muscles by examining descending efferent and contralateral projections of the sites within the medullary reticular formation (MRF) that evoke EMG responses in lumbar axial muscles upon electrical stimulation. In the first series of experiments, retrograde tracers were deposited at gigantocellular reticular nucleus (Gi) sites that excited the back muscles and in the contralateral lumbar spinal cord. The medullary reticular formation contralateral to the Gi stimulation/deposition site was examined for the presence of single- and double-labeled cells from these injections. Tracer depositions into Gi produced labeled cells in the contralateral Gi and Parvocellular reticular nucleus (PCRt) whereas the lumbar injections retrogradely labeled cells only in the ventral MRF, indicating that separate populations of medullary reticular cells project to the opposite MRF and the lumbar cord. In the second series of experiments the precise relationships between the location of neurons retrogradely labeled from lumbar spinal cord depositions of the retrograde tracer, Fluoro-Gold (FG) and effective stimulation tracks through the MRF were examined. The results indicate that the Gi sites that are most effective for activation of the back muscles are dorsal to the location of retrogradely labeled lumbar reticulospinal cells. To verify that cell bodies and not fibers of passage were stimulated, crystals of the excitatory amino acid agonist, N-methyl-d-asparate (NMDA) were deposited at effective stimulation sites in the Gi. NMDA decreased the ability of electrical stimulation to activate back muscles at 5 min postdeposition, indicating a local interaction of NMDA with cell bodies at the stimulation site. In the third series of experiments, electrical thresholds for EMG activation along a track through the MRF were compared to cells retrogradely labeled from FG deposited into the cervical spinal cord. In some experiments, Fast Blue was also deposited into the contralateral lumbar cord. Neurons at low threshold points on the electrode track were labeled following cervical depositions, indicating a direct projection to the cervical spinal cord. The lumbar depositions, again, labeled cells in MRF areas that were ventral to the locations of effective stimulation sites, primarily on the opposite side of the medulla. In addition, the lumbar depositions back-filled cells in the same cervical segments to which the Gi neurons project. These results suggest that one efferent projection from effective stimulation sites for back muscle activation is onto propriospinal neurons in the cervical cord, which in turn project to lumbar cord levels. In a final series of experiments, a stimulating electrode track through the MRF again identified low threshold and ineffective sites for activating lumbar epaxial EMG. Fluoro-Gold was deposited in the contralateral MRF (MRFc) at a low threshold stimulation site for activating back muscles on that side. Retrogradely labeled cells surrounded effective, but not ineffective, stimulation sites along the electrode track in the MRF. Thus, another projection from effective stimulation sites is to effective stimulation sites in the opposite MRF. These results suggest that neurons in Gi whose stimulation most effectively activates back muscle EMG do not project directly to the lumbar cord, but relay to cervical cord neurons, which in turn project onto lumbar neurons. The MRF commissural connections presumably amplify this descending MRF control of axial back muscles.
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    Experimental brain research 92 (1992), S. 259-266 
    ISSN: 1432-1106
    Keywords: Hypoglycemia ; Neuronal death ; N-methyl-D-aspartate ; AMPA ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg · kg-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h), with dizocilpine 0.33 mg · kg-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] 10 mg · kg-1 given i.p.. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist. We conclude that neuronal damage continues to develop in the striatum and in cortical brain regions in the posthypoglycemic period and that both NMDA- and AMPA-receptors contribute to this process, possibly by a change in the cellular response to both AMPA- and NMDA-receptor stimulation.
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  • 128
    ISSN: 1432-1106
    Keywords: Genetically epilepsy-prone rat ; Blood-brain barrier ; Local cerebral glucose utilization ; Thyroid hormones ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The genetically epileptic-prone rat (GEPR) is a valuable model for the study of gene-linked abnormalities involved in epilepsy. In comparison with normal Sprague-Dawley controls, we found, in GEPRs, a marked depression in local cerebral glucose utilization, widespread throughout the brain. This depression was accompanied by a significant increase of blood-brain barrier permeability and a reduction in regional blood volume. Finally GEPRs showed lower plasma levels of total triiodothyronine than normal controls. One can speculate that alterations in cerebral metabolism and microvascular regulation and thyroid hormone imbalance may be gene-linked factors involved in seizure susceptibility.
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  • 129
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    Experimental brain research 88 (1992), S. 67-77 
    ISSN: 1432-1106
    Keywords: Retina ; Ganglion cells ; Alpha cells ; Lucifer yellow ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The somato-dendritic morphologies of large ganglion cells were studied by intracellular injections of Lucifer yellow in perfusedin vitro preparations of the albino rat retina. The ganglion cells were prelabeled with retrogradely transported granular blue or labeled with acridine orange dropped into the perfusate ofin vitro preparations. After the dye injection, somato-dendritic morphologies were successfully studied for 210 cells, the majority of which had a large soma more than 20 µm in diameter and were identified as alpha cells. According to the level of dendritic extensions within the inner plexiform layer (IPL) these alpha cells were further classified into inner ramifying (inner) and outer ramifying (outer) cells. Both qualitative and quantitative observations led us to conclude the following:1) The outer cells have a spherical soma with relatively few primary dendrites, while inner cells have a large polygonal soma with more primary dendrites.2) The dendritic field of inner cells was always larger than that of outer cells at every retinal location. The dendritic field diameter tended to increase as a function of retinal eccentricity from the optic disk, the tendency being more clear among inner cells.3) The dendrites of outer cells branch more frequently in the proximal part of the dendritic field while those of inner cells branch more distally.4) Total dendritic length of outer cells increases linearly with eccentricity whereas that of the inner cells does not change much irrespective of retinal location.
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  • 130
    ISSN: 1432-1106
    Keywords: Ischemia ; Brain damage ; Substantia nigra pars reticulata ; Excitatory amino acids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Preischemic hyperglicemia worsens brain damage after ischemia, and characteristically leads to post-ischemic seizures and a pan-necrotic lesion in substantia nigra pars reticulata (SNPR). The excitatory input to SNPR could contribute to the damage observed. By performing a unilateral frontal cortex lesion 6–19 days prior to the ischemia, we wanted to explore whether a decrease in excitatory input to the ipsilateral SNPR ameliorate the seizures or alter the light microscopical damage in SNPR. Our results demonstrate that unilateral frontal cortex lesion did not alter the development of fatal post-ischemic seizures after 10 min of ischemia in hyperglycemic subjects. Thus, 7/8 animals developed seizures and died within 20 h of recovery. This study also failed to show any difference between the left and right side in post-ischemic SNPR damage after 15 h of recovery in animals with preischemic unilateral frontal cortex lesion. Furthermore, no side difference was observed in any other brain region evaluated. The results thus suggest that the pan-necrotic lesion in SNPR after hyperglicemic ischemia is not caused by excessive excitatory input from frontal cortex. A decrease in the GABA-ergic inhibitory input from caudoputamen to SNPR may be a more important mechanism for the ensuing excitotoxic post-ischemic SNPR damage, and for seizure development.
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  • 131
    ISSN: 1432-1106
    Keywords: Supraoptic nucleus ; Dynorphin ; Opioids ; Neurohypophysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Studies performed in conscious female rats confirmed that iv injection of cholecystokinin octapeptide (CCK; 20µ/kg) increased the circulating concentration of oxytocin but not that of vasopressin, and confirmed that the stimulation of oxytocin release was markedly facilitated after iv administration of naloxone (1mg/kg), indicating attenuation of oxytocin release by endogenous opioids. To investigate the site of action of the endogenous opioids, the electrical activity of putative oxytocin neurones in the supraoptic nucleus was recorded in urethaneanaesthetised female rats. Oxytocin neurones responded to CCK injection with an increase in firing rate lasting 5–15 min, but this response was not facilitated by prior injection of naloxone. The results suggest that the opioid influence upon CCK-induced oxytocin release operates at the level of the neurosecretory terminals in the neurohypophysis rather than centrally. Since CCK does not elevate vasopressin release, it appears unlikely that dynorphin, the opioid peptide co-existing with vasopressin, is responsible in these circumstances for the cross-inhibition of oxytocin release. It is suggested that products of proenkephalin A, the met-enkephalin precursor present in the supraoptic nucleus and in the neurohypophysis itself, may be active in the regulation of oxytocin release.
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  • 132
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    Experimental brain research 88 (1992), S. 541-550 
    ISSN: 1432-1106
    Keywords: Superior colliculus ; Intralaminar thalamus ; Tectal stimulation ; Somatosensory responses ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The intralaminar thalamus of anesthetized rats was explored for neurons activated by stimulation of the superior colliculus and responsive to sensory inputs. Neurons activated by stimulation of the intermediate and deep collicular layers were distributed throughout the intralaminar thalamus. Approximately one half of them responded to tectal as well as sensory inputs. The majority were nociceptive or had a more complex response pattern including responses to auditory stimulation. A smaller population of low threshold units had contralateral orofacial receptive fields and responded to light taps; these units were preferentially localized anteriorly in the central lateral and paracentral nuclei. Neurons responsive to tectal and sensory stimulation were randomly intermingled with other neurons which had no detectable sensory input. The results indicate that ascending projection neurons of the intermediate and deep layers of the superior colliculus provide an input to functionally diverse subpopulations of intralaminar thalamic neurons. In view of its projections to motor cortex and basal ganglia, the intralaminar thalamus appears directly implicated in basal ganglia and superior colliculus related mechanisms of attention, arousal and postural orienting.
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  • 133
    ISSN: 1432-1106
    Keywords: Vision ; Excitatory amino acids ; Thalamocortical connections ; Intrinsic connections ; Visual cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To examine the organization of axon collaterals of neurons that selectively take up and transport excitatory amino acids, we have used retrograde tracing with D-[3H]Aspartate after injections into different layers of rat primary visual cortex. The results show cells in the lateral geniculate nucleus retrogradely labeled from the cortex. Additional topographically precise input to the thalamic recipient layer 4 originates from neurons in the visual cortex lying in layers 2/3, 5 and 6. These inputs are reciprocated by point-to-point projections from layer 4. Layer 2/3 cells project to layers 5 and 6 in columnar fashion. Putative excitatory input to layer 2/3 originates from a vertical column of cells in layer 5 and the middle of layer 6. In addition layer 2/3 receives input via horizontal collaterals of topographically distant upper layer neurons, from more widespread projections in lower layer 6, and from very widespread projections of cells at the layer 5/6 border. Cells in the depth of layer 5 also distribute collaterals within layers 5 and 6. Our findings provide anatomical evidence that the geniculo-cortical pathway in the mammalian visual system may use excitatory amino acid transmitters. In addition, the results support the notion that most long range connections that link distant points of the topographic map are excitatory.
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  • 134
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    Experimental brain research 89 (1992), S. 67-78 
    ISSN: 1432-1106
    Keywords: Cerebral ischemia ; Experimental stroke ; Recirculation ; Cerebral blood flow ; Brain damage ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It has become increasingly clear that a stroke lesion usually consists of a densely ischemic focus and of perifocal areas with better upheld flow rates. At least in rats and cats, some of these perifocal (“penumbral”) areas subsequently become recruited in the infarction process. The mechanisms may involve an aberrant cellular calcium metabolism and enhanced production of free radicals. In general, though, the metabolic perturbation in the penumbra requires better characterization. The objective of this article was to define flow distribution in a rat model of reversible middle cerebral artery (MCA) occlusion, so as to allow delineation of the metabolic aberrations responsible for the subsequent infarction. We modified the intraluminal filament occlusion model recently developed by Koizumi et al. (1986), and described in more detail by Nagasawa and Kogure (1989), adopting it for use in both spontaneously breathing and artificially ventilated rats. Successful occlusion of the MCA (achieved in about 9/10 rats) was judged by unilateral EEG depression in ventilated rats, and neurological deficits, such as circling, in spontaneously breathing ones. CBF in the ipsilateral hemisphere was reduced to nearly constant values after 20, 60, and 120 min of occlusion, flow rates in the focus being about 10% and in the perifocal ipsilateral areas about 15–20% of control (contralateral side). When the filament was left in place (permanent occlusion) 2,3,5-triphenyl tetrazolium chloride (TTC) staining and histopathology after 24 h showed a massive infarct on the occluded side, extending from caudoputamen and overlaying cortex to the occipital striate cortex. Animals recirculated after 60 min of MCA occlusion, and allowed to survive 7 days for histopathology, showed infarction of the caudoputamen (lateral part or whole nucleus) in 5/6 animals and selective neuronal necrosis in one animal. The neocortex showed either infarcts, selective neuronal necrosis, or no damage. There was some overlap between neocortical areas which were infarcted and those which were salvaged by reperfusion. In general, though, both the CBF data and the recovery studies with a histopathological endpoint define large parts of the neocortex as perifocal (penumbral) areas which lend themselves to studies of metabolic events leading to infarction.
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    Experimental brain research 89 (1992), S. 133-139 
    ISSN: 1432-1106
    Keywords: Defence response ; Ventrolateral periaqueductal grey matter ; Rostral ventrolateral medulla ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In rats anaesthetised with alphaxalone/alphadolone, electrical stimulation in the dorsal periaqueductal grey matter (PAG) evoked a presser response with tachycardia, vasodilatation in the hindlimb and hyperpnoea: a pattern of response known as the defence reaction. Microinjection of the synaptic excitant, D,L-homocysteic acid (DLH), but not saline, into the ventrolateral PAG at the level of the decussation of the superior cerebellar peduncle (approximately 7.3–8.3 mm caudal to bregma) produced a reduction in the size of the cardiovascular components of the defence reaction evoked by electrical stimulation in the dorsal PAG. Injections of DLH made outside this region had no effect on the defence response. Injection of DLH into the “defence inhibition area” had no effect on the presser response evoked distally in the efferent pathway for the defence reaction, by electrical stimulation in the rostral ventrolateral medulla (RVLM). Activation of neurones in a restricted portion of the caudal ventrolateral PAG appears to modulate activity in the descending pathway for the defence response evoked from the dorsal PAG. It is argued that the inhibitory interaction probably occurs at the level of synapses in the RVLM.
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  • 136
    ISSN: 1432-1106
    Keywords: Cerebellum ; Nucleus lateralis ; Rat ; Motor organization ; Microstimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The motor organization of the nucleus lateralis (NL) of the rat's cerebellum was investigated by observing the motor effects of electrical microstimulations of the NL. The movements evoked by the NL mainly concerned forelimb and head segments. Only in a few cases were movements of hindlimb segments evoked. Motor effects were obtained according to a precise topographical pattern. This pattern delimited functional zones, or representations, within the NL, each zone being specifically related to a particular segment of the body. A few body segments were activated from single zones only (single representation) whereas some other body segments could be activated from different zones of the NL. Among them, the axio-proximal body segments were activated in a similar way from all sites (multiple representation) whereas the distal body segments were differently activated from the various representation zones (specific representation). The multiple and specific representations were distributed between the 3 cytoarchitectonic subregions of the NL (NLm, DLH and slp) in such a way that the body segments were usually represented only once in each individual NL subregion. Each NL subregion included sets of representations concerning body segments characterized by a topographical continuity (e.g. the different segments of the forelimb in both DLH and slp). Thus, the individual NL subregions may bring into play coordinate plurisegmental muscular activities of the limbs and/or of the head. The NLm controls movements of all the segments of the head and those of axio-proximal segments of both limbs. The DLH particularly controls movements of the head, including both the proximal (neck) and the oral regions. To a lesser degree, DLH controls movements of the various segments of the forelimb, including synchronous flexion of all the digits. The slp is specifically involved in the control of motor activities of: i) the proximal segment of the head (rotation of the neck) as well as its distal segments (displacement of individual vibrissae, rotation of the ear pinna) and ii) the various segments of the forelimb including individual digits. Functionally, the proximal segments would be concerned in the spatial displacement of the limbs or of the head whereas the distal segments would be involved in the realization of precise and discrete movements related to specific functions of the distal segments concerned. The 3 subregions of the NL may be concerned in different motor functions. The results suggest the involvement of: i) the NLm in the postural adjustments of the body, or of part of it; ii) the DLH in motor behaviours which integrate the oral and the forelimb motor activities; iii) the slp in exploratory activities (by moving individual vibrissae, the ear pinna and individual digits) and/or in discrete manipulative activities.
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  • 137
    ISSN: 1432-1106
    Keywords: Miniature EPSP ; Spinal cord cultures ; Motoneuron ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Miniature excitatory postsynaptic potentials (mEPSPs) were recorded in motoneurons grown in organotypic cocultures of embryonic rat spinal cord, dorsal root ganglia and muscle in the presence of TTX. The motoneurons were electrically compact with a mean electrotonic length of 0.6. Spontaneous EPSPs were found in most of these motoneurons. With TTX the large EPSPs disappeared, whereas in more than half of the experiments mEPSPs persisted with a range in size of 1 to 4 mV (mean: 2.1 mV), probabely originating from the spontaneous release of single vesicles. The net inward charge transfer at the soma ranged from 0.12 to 0.34 pC. The mEPSPs were heterogeneous in size even within pools of potentials that were homogeneous in shape. They had similar shapes and amplitudes as the smallest spontaneous unitary EPSPs mediated by presynaptic impulses, suggesting that for the smallest afferents not more than one vesicle was released per afferent impulse. Both the miniature and the TTX-sensitive EPSPs were readily blocked by the glutamate antagonist DNQX.
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  • 138
    ISSN: 1432-1106
    Keywords: Colchicine ; Choline acetyltransferase ; Cholinergic degeneration ; Phosphoinositide hydrolysis ; Cytoskeletal proteins ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Colchicine, a microtubule disrupting toxin, was administered intracerebroventricularly to rats, followed by measurements of (i) the activity of choline acetyltransferase, a biochemical marker of cholinergic neurons, (ii) cytoskeletal protein concentrations, including tau, MAP-2, spectrin, and tubulin, and (iii) the activity of the second messenger-generating system, receptor-coupled phosphoinositide hydrolysis. One week after colchicine treatment there was a 60% decrease in choline acetyltransferase activity in the hippocampus, which was followed by a gradual increase to only a 29% deficit after 12 weeks. In the striatum and cerebral cortex, choline acetyltransferase activity was slightly reduced (by 13% and 19%, respectively) 1 week after colchicine treatment followed by increases to control values. The concentrations of tau and tubulin in the hippocampus were unaltered by colchicine treatment, and MAP-2 and spectrin were only slightly reduced 4 weeks after colchicine. Hippocampal phosphoinositide hydrolysis induced by norepinephrine was elevated approximately 28% 1 and 2 weeks after colchicine treatment and that induced by ibotenate was increased by 53% 2 weeks after colchicine. These results demonstrate that colchicine causes a severe depletion of choline acetyltransferase 1 week after administration. There was not a significant reduction of the concentration of any of the cytoskeletal proteins after 1 week, possibly due to the cell-selectivity of the toxic effect of colchicine, but there was a delayed, and temporary, decline of MAP-2 and spectrin concentrations. Associated with the decreased choline acetyltransferase activity after 1 week was an enhanced phosphoinositide hydrolysis in response to norepinephrine, and after 2 weeks there were enhanced responses to norepinephrine and to ibotenate. Thus, colchicine-induced toxicity results in neurotransmitter- and time-specific alterations in the activity of the phosphoinositide second messenger-generating system in the hippocampus.
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  • 139
    ISSN: 1432-1106
    Keywords: Basic fibroblast growth factor ; Forebrain ischemia ; Astrocyte ; Immunoreactivity ; mRNA level ; Hippocampus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We examined the time course of basic fibroblast growth factor (bFGF) immunoreactivity and its mRNA level mainly in the hippocampus after transient forebrain ischemia using immunohistochemistry, enzyme immunoassay (EIA), Western blot analysis and in situ hybridization. Neuronal death in the hippocampal CA1 subfield was observed 72 h after 20 min of ischemia. The number of bFGF-immunoreactive(IR) cells increased 48 h–5 days after ischemia in all hippocampal regions. At 10 and 30 days, the bFGF-IR cells in the CA1 subfield had further increased in numbers and altered their morphology, enlarging and turning into typical reactive astrocytes with the advancing neuronal death in that area. In contrast, the number of bFGF-IR cells in other hippocampal regions had decreased 30 days after ischemia. The EIA study showed a drastic increase in bFGF levels in the hippocampus 48 h after ischemia (150% of that in normal rat) which was followed by further increases. In Western blot analysis, three immunoreactive bands whose molecular weights correspond to 18, 22 and 24 kDa were observed in normal rat and ischemia increased all their immunoreactivities. In the in situ hybridization study of the hippocampus, bFGF mRNA positive cells were observed in the CA1 subfield in which many bFGF-IR cells existed after ischemia. These data demonstrate that transient forebrain ischemia leads to an early and strong induction of bFGF synthesis in astrocytes, suggesting that the role of bFGF is related to the function of the reactive astrocytes which appear following brain injury.
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  • 140
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    Experimental brain research 90 (1992), S. 11-20 
    ISSN: 1432-1106
    Keywords: Homocysteic acid ; Cerebellum ; Taurine ; Glial cells ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An antiserum to homocysteic acid was raised in rabbits. Immunogens were prepared by coupling this amino acid to bovine serum albumin by means of glutaraldehyde and paraformaldehyde. When applied to semithin or ultrathin sections of rat cerebellum, the antiserum produced selective labelling of glial cells and processes, including the Bergmann fibers. No enrichment of immunoreactivity was detected in nerve terminals of the major excitatory fiber systems. The distribution of homocysteic acid-like immunoreactivity was very different from that of taurine (another sulphur-containing amino acid), as judged from consecutive semithin sections labelled with a postembedding immunoperoxidase procedure and from ultrathin sections labelled with a postembedding double immunogold procedure. Taurine-like immunoreactivity was concentrated in Purkinje cells and was low in glial elements. Our data suggest that the cerebellum contains a glial pool of homocysteic acid (and/or precursors that may undergo spontaneous oxidation to homocysteic acid) and that this amino acid is unlikely to act as a cerebellar transmitter.
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  • 141
    ISSN: 1432-1106
    Keywords: Methylazoxymethanol acetate ; Microencephaly ; Choline acetyltransferase ; Substance P ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The habenulo-interpeduncular system of the rat constitutes an interesting model to address quantitatively problems related to synaptogenesis and to the interactions between neuronal populations after selective alteration of these elements during development. In the present study this has been achieved by experimentally reducing, through gestational treatment with methylazoxymethanol acetate (MAM), the population of cholinergic neurons of the medial habenula which projects to the interpeduncular nucleus. Immunohistochemical analysis gave evidence that the topographical localization of the cholinergic and the substance P-containing populations in the medial habenula was not altered by MAM treatment. Furthermore, the topographical distribution of cholinergic fibers and terminals in the interpeduncular nucleus, which reflects the habenulo-interpeduncular projection as well as cholinergic projections coming from different sources, was substantially preserved. The same was also true concerning the terminal distribution of substance P in the interpeduncular nucleus. Quantitative radioassays demonstrated a sizable decrease of overall ChAT activity in both the habenulae and the interpeduncular nucleus. By comparison of 1 month-old and 3 month-old animals it appeared that this effect was partially reversed with age in the interpeduncular nucleus.
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  • 142
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    Experimental brain research 90 (1992), S. 141-146 
    ISSN: 1432-1106
    Keywords: Spike train ; Pattern recognition ; Hippocampal neurons ; Spontaneous activity ; Cell culture ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Spontaneous activity and rhythmical oscillations are common features of large neuronal networks in mammals. Detection of repetitive spike patterns or pacemaker activity during electrophysiological recording of spontaneous action potentials from single neurons can be difficult if a “noisy” background is present. This paper describes an improved method for an online spike train analysis based on joint interval histograms (JIH, Rodiek et al. 1962). By means of higher ordered JIH the discrimination of spike patterns with repetitive bursting activity or oscillations is possible even when randomly distributed action potentials appear. Examples of simulated spike trains and those recorded from cultured hippocampal neurons are presented.
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  • 143
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    Experimental brain research 90 (1992), S. 275-290 
    ISSN: 1432-1106
    Keywords: Movement ; Sequence ; Basal ganglia ; Frontal cortex ; Cerebellum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats emit grooming actions in sequences that follow characteristic patterns of serial order. One of these patterns, a syntactic chain, has a particularly stereotyped order that recurs spontaneously during grooming thousands of times more often than could occur by chance. Previous studies have shown that performance of this sequence is impaired by excitotoxin lesions of the corpus striatum. In this study we examined whether the striatum is unique in its importance to this behavioral sequence or whether control of the sequence instead depends equally upon the cortex and cerebellum. In two experiments, a fine-grained behavioral analysis compared the effects of striatal ablation to the effects of motor cortex ablation, ablation of the entire neocortex, or ablation of the cerebellum. Cortical and cerebellar aspiration produced mere temporary deficits in grooming sequences, which appeared to reflect a general factor that was nonsequential in nature. Only striatal damage produced a permanent sequential deficit in the coordination of this syntactic grooming chain. We conclude that the striatum has a unique role in the control of behavioral serial order. This striatal role may be related to a number of sequential disorders observed in human diseases involving the striatum.
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  • 144
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    Experimental brain research 90 (1992), S. 291-296 
    ISSN: 1432-1106
    Keywords: Cholinergic systems ; Acetylcholinesterase ; Choline acetyltransferase ; Superior colliculus ; Guinea pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied the distribution of acetylcholinesterase activity and choline acetyltransferase immunoreactivity in the superior colliculus of the guinea pig and the albino rat, using enzyme histochemical and immunohistochemical methods. Choline acetyltransferase-like immunoreactivity was localized in the neuropil throughout the colliculi, but the density of the immunoreactive neuropil varied among layers as well as between species. In the intermediate collicular layers the pattern of choline acetyltransferase immunoreactivity was closely matched by the distribution of acetylcholinesterase activity in guinea pig and rat, confirming our previous findings in the cat. Furthermore, in the guinea pig, but not in the rat, choline acetyltransferase-like immunoreactivity was localized in a prominent population of perikarya of the superficial gray layer.
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  • 145
    ISSN: 1432-1106
    Keywords: Synaptic-Plasticity ; Cerebellum ; Metabotropic-glutamate-receptor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Using an in vitro slice preparation, we studied the effects, on parallel fiber (PF)-mediated EPSPs, of coactivation of metabotropic-glutamate receptors and of voltage-gated calcium (Ca) channels of Purkinje cells (PCs) by bath application of 50 μM trans-1-aminocyclopentyl-1,3-dicarboxylate (trans-ACPD) and by direct depolarization of the cells, respectively. These effects were compared with changes in synaptic efficacy obtained when α-amino-3hydroxy-5-methylisoxalone-4-propionate (AMPA) receptors of PCs were also activated through stimulation of PFs during the pairing protocol, as well as when similar experiments were performed without trans-ACPD in the bath. In a control medium, pairing for 1 min of PF-mediated EPSPs evoked at 1 Hz with Ca spikes evoked by steady depolarization of PCs (n = 13) led to LTD of synaptic transmission in 9 cases whereas for the others EPSPs were not affected. No LTD occurred in 9 out of 10 other cells tested when PF stimulation was omitted during the 1 min period of Ca spike firing of PCs. Bath application of 50 μM trans-ACPD, in conjunction with the same pairing protocol as before (n = 8), led to a significantly larger LTD of PF-mediated EPSPs after washing out of this drug. Moreover, a clearcut LTD of PF-mediated EPSPs was also observed in 5 of the 8 other cells, when PF stimulation was omitted during Ca spike firing in the presence of trans-ACPD. As trans-ACPD alone induced fully reversible depressions of EPSPs, coactivation of metabotropic-glutamate receptors and of voltage-gated Ca channels is therefore likely to be sufficient to induce LTD of PF-mediated EPSPs.
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  • 146
    ISSN: 1432-1106
    Keywords: Retina ; Transplant ; Parvalbumin ; Immunocytochemistry ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Retinas from embryonic day 14 Sprague-Dawley rats were transplanted to the midbrain or cerebral cortex of newborn (P0) rats of which the right eye was enucleated at the time of transplantation. Parvalbumin immunoreactive (PV-I) neurons were studied in the developing retinal transplants, and in the remaining retina of the host, as well as in normal retinas. PV-I neurons were identifiable in retinas of normal and host rats from postnatal day 5 (P5) onward, with the PV-I somata primarily in the inner half of the inner nuclear layer and in the ganglion cell layer. An adult-like distribution of PV-I neurons was attained at P35, as judged by cell packing density, intensity of immunostaining, laminar distribution and soma size of subpopulations of PV-I cells. A similar time course of development and distribution of PV-I somata was observed in the retinal transplants, except for some minor differences such as a slight delay in PV-I cells achieving their final distribution. These findings provide evidence that PV-I neurons can survive, differentiate and mature according to pre-determined programmes intrinsic to the retinal tissue following transplantation to a new and foreign environment.
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  • 147
    ISSN: 1432-1106
    Keywords: Brain ischemia ; Idazoxan ; Metabolism ; Noradrenaline ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The brain noradrenaline (NA) system is known to modulate ischemic neuronal damage, and the turnover of NA has been suggested to increase in the early recovery period following cerebral ischemia. Using HPLC and gas chromatography-mass spectrometry we analyzed the tissue levels of NA and its metabolites, 3,4-dihydroxyphenylethyleneglycol (DHPG) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), in rat brain cortex after 10 min of forebrain ischemia followed by 1 h of recirculation. The effect of idazoxan, given in cerebro-pbrotective doses, as a bolus of 0.1 mg·kg-1 immediately after ischemia followed by 10 μg·kg-1·min-1 for 1 h, was also investigated. Ischemia decreased basal NA cortical levels from 384 ng/g tissue in control animals to 214 ng/g, while DHPG increased from 74 to 103 ng/g (+39%) and MHPG from 82 to 154 ng/g (+88%). Conjugated but not free DHPG increased, while both free and conjugated MHPG increased equally. The findings indicate an enhanced postischemic NA turnover with a major proportion of uptake and metabolism occurring extraneuronally, possibly secondary to a saturation of neuronal NA uptake in the postischemic phase. Idazoxan further increased NA turnover, as evidenced by higher postischemic levels of free MHPG and a higher MHPG/NA ratio. A correlation may exist between the protective action of idazoxan and its effect on NA turnover.
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  • 148
    ISSN: 1432-1106
    Keywords: Vibrissae ; Somatosensory system ; Cortical columns ; Receptive field ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A “barrel” is an interconnected network of layer IV neurons that is an important component of a functional cortical column in the whisker area of the rodent primary somatosensory cortex. The present study was undertaken in order to resolve apparently conflicting findings from single-unit studies of barrel neurons conducted in rats maintained under different anesthetic conditions. Multiunit responses to controlled deflections of mystacial vibrissae were recorded from the whisker/ barrel cortex of awake, undrugged rats, and responses at the same recording site were reexamined after the animal was anesthetized with urethane. In contrast to the awake condition, stimulus-evoked responses under urethane were characterized by a large late component. Such effects were more pronounced for deflections of noncolumnar or “adjacent” whiskers than for the the columnar whisker. Latencies to peak responses were virtually identical for the columnar whisker in awake and urethane states (11.9 vs 11.8 ms) but were considerably longer for adjacent whisker deflections in urethane-anesthetized animals (15.5 vs 29.0 ms). The magnitudes of adjacent whisker responses, relative to the response evoked by the columnar whisker, varied with the laminar location of the recording site in awake but not in urethane-anesthetized animals; in awake rats, receptive fields were clearly smallest in the layer IV barrels. Results in the awake condition confirm those of previous studies conducted in unanesthetized or lightly sedated animals, and data obtained with urethane are comparable to others' results in urethane-anesthetized rats. The former have important implications for how barrel cortex processes information in behaving animals.
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  • 149
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    Experimental brain research 91 (1992), S. 408-414 
    ISSN: 1432-1106
    Keywords: Taste ; Cortex ; Receptive fields ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Receptive fields (RFs) of 59 cortical taste neurons (35 in the granular insular area, area GI, 21 in the dysgranular insular area, area DI, and 3 in the agranular insular area, area AI) were identified in the oral cavity of the rat. The fraction of the neurons with RFs in the anterior oral cavity only was significantly larger in area GI (74.3%) than in area DI (42.9%). On the other hand, the fraction of neurons with RFs in both the anterior and posterior oral cavity was larger in area DI (42.9%) than in area GI (11.4%). On the whole, it is suggested that area GI is involved in discrimination of several taste stimuli in the oral cavity, whereas in area DI taste information originating from various regions of the oral cavity is integrated. When neurons were classified according to the best stimulus which most excited the neuron among the four basic tastes, different categories of taste neurons had RFs in different parts of the oral cavity. It is suggested that, in either taste area, different categories of taste neurons are involved in different sorts of taste coding. The majority of neurons in both areas had bilateral RFs. In area GI, neurons with RFs on single subpopulations of taste buds were significantly more numerous at the rostral region of the cortex than at the caudal region. There was no such relation between RF types and cortical localization in area DI. Otherwise, topographic representation of the oral cavity by taste neurons on the cortical surface was not obvious. RF features of taste neurons did not differ across layers in either cortical area.
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  • 150
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    Experimental brain research 91 (1992), S. 477-483 
    ISSN: 1432-1106
    Keywords: Transplantation ; Neocortex ; Parvalbumin and calbindin immunocytochemistry ; Numerical density ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Numerical density and morphology of the two main GABAergic neuronal classes, the parvalbumin (PV) and calbindin- (CaBP)-containing nerve cells were investigated in long-term neocortical transplants in rats. It was observed that 4 months after the transplantation both CaBP- and PV-immunoreactive neurons survive and grow in neocortical grafts. However, the numerical density of PV cells decreased to about half of the control value (host cortex), while the density of CaBP-positive cells was 25–60% of that seen in the host cortex, depending on the degree of integration of the graft. The mean diameter of PV neurons rose to double of the control value, while the size of CaBP-positive perikarya did not change. This indicates that GABAergic neurons with hypertrophic perikarya (Bragin et al. 1991a) are identical to PV neurons. On the basis of these qualitative and quantitative morphological data it is concluded that PV- and CaBP-containing GABA cells in the transplant exhibit different sensitivities to transplantation-related structural and functional alterations.
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  • 151
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    Experimental brain research 91 (1992), S. 489-495 
    ISSN: 1432-1106
    Keywords: Regulation ; Synthesis ; Release ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the urethane-anesthetized rat, electrical stimulation (10 Hz, 30 s, 250 μA) of the medial forebrain bundle (MFB), at 20-min intervals over an 8-h period, combined with intracerebral microdialysis in the striatum caused: an undiminished increase in the release of dopamine (DA) with each stimulation episode; a decreased efflux of 3,4-dihydroxyphenylacetic acid (DO-PAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) after the first stimulation only; a delayed increased efflux of DOPAC with no change in HVA; and a poststimulation depression of firing of dopaminergic neurons in the substantia nigra (before, 3.1±0.7 Hz; after, 1.9±1.0 Hz; P〈0.05). After the last stimulation episode, the release of DA declined to prestimulation values, while the increased efflux of DOPAC persisted for three more hours. After the infusion of tetrodotoxin (4.0×10-7 M, 1.5 μl, 1.0 μl/min) into the MFB, the basal release of DA was reduced (P〈0.05), while the efflux of DOPAC and HVA was increased (P〈0.05). A model is proposed suggesting that: (1) during increased release of DA in the striatum, the metabolism of DA is decreased; (2) inhibition of nigrostriatal dopaminergic neurons is the usual cause of increased synthesis and metabolism of DA in the striatum; and (3) increased release of DA, and increased synthesis and metabolism of DA in the striatum are not causally linked and are noncoupled processes.
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  • 152
    ISSN: 1432-1106
    Keywords: Nociceptor ; Bradykinin ; Serotonin ; Substance P ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A broad mixture of inflammatory mediators (“inflammatory soup”) was used to investigate the responsiveness of primary afferents from rat hairy skin in an in vitro skin-saphenous nerve preparation. In addition, a conditioning effect of the tachykinin substance P on chemosensitivity of nociceptors was examined. Inflammatory soup (IS) was made up in synthetic interstitial fluid from bradykinin, serotonin, histamin and prostaglandin E2 (all 10-5 M). In addition, the potassium and the hydrogen ion concentration (7 mM, pH 7.0) and the temperature (39.5°C) were elevated. The latter agents, in a control solution, did not excite nociceptors (n = 5). IS was repeatedly superfused over the receptive fields for 5 min at 10 min intervals; substance P (SP 10-6 and 10-5 M) was applied during the last 5 min of the interval and during the subsequent IS stimulation. IS excited more than 80% of the mechano-heat sensitive (“polymodal”) afferents with slowly conducting nerve fibres (n = 72), but none of the low-threshold mechanoreceptive slow and fast conducting units (n = 17). Slow conducting afferents with high mechanical threshold (n = 35) were weakly, and less frequently (〈20%), driven by IS. A majority, but not all, of the responsive units showed tachyphylaxis upon repeated IS application. None, however, lost its responsiveness completely. Conditioning heat stimulation (32–46.5°C in 20 s) did not enhance the subsequent IS response, which may indicate that sensitizing substances normally released by a noxious heat stimulus were already contained in IS. No sensitization to mechanical (von Frey) or heat stimulation could be established in the period after the IS response had subsided and after the washout was completed, respectively. A short-lived sensitization may have been overlooked under these temporal restrictions. Conditioning SP in 10-5 M but not in 10-6 M concentration significantly increased the IS response of polymodal C fibres, by 58% on average (n = 14). SP did not excite the units. Comparing with previous data, we conclude that there is a significant synergism between inflammatory mediators, acting to induce more intense and more sustained discharge via many nociceptors than single mediators alone could achieve. Conditioning substance P can further enhance this algogenic action. Mechanisms of interaction and relative contributions of single substances remain to be elucidated.
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    Experimental brain research 92 (1992), S. 69-78 
    ISSN: 1432-1106
    Keywords: Kindling ; Reactive sprouting ; Dendritic spines ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A Golgi and electron microscopy study of the hippocampal CA3 region was performed on control and kindled Wistar rats. The observations provide evidence that, in epileptic rats, mossy fibres sprout and establish novel synapses with the basilar dendrites of CA3 pyramidal neurons. These newly-developed synapses showed the typical features of mossy synapses observed in the stratum lucidum, including the appearance of complex giant spines. The morphological changes reported here may represent a histopathological substrate for the epilepsy in the absence of overt signs of a hippocampal lesion.
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  • 154
    ISSN: 1432-1106
    Keywords: Anterograde axonal tracing ; Brain repair ; Neocortical projections, injury, and transplants ; Phaseolus vulgaris-leucoagglutinin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fetal rat neocortex grafted into lesion cavities made in the newborn rat neocortex can exchange multiple axonal connections with the host brain. Most previous studies demonstrating efferent transplant-tohost brain connections have used fluorescent retrograde tracers injected into the host brain (Castro et al. 1985, 1987; Floeter and Jones 1984; O'Leary and Stanfield 1989). Other studies have used anterograde axonal tracing with either tritium-labelled amino acids impregnating the transplant and its efferents (Floeter and Jones 1985) or horseradish peroxidase injected into the transplants (Chang et al. 1984, 1986). In the present study we used the anterograde axonal tracer Phaseolus vulgaris — leucoagglutinin (PHA-L) to examine in detail the course and termination of the efferent neocortical graft fibers. Twenty-six newborn rats had the right frontal cortex forepaw area removed by vacuum aspiration, while anesthetized by hypothermia. A piece of fetal frontal cortex 14–16 embryonic days old (E14–16) was immediately thereafter placed in the lesion, and the recipient rats allowed to survive for 5–7 months. At this time the rats were reoperated under sodium pentobarbital (Nembutal) anesthesia and the transplants iontophoretically injected with PHA-L. Two weeks later the animals were again anesthetized, perfused, and processed for PHA-L immunocytochemistry and routine histology. Analysis of acetylcholinesterase- (AChE) and Nissl-stained sections showed graft survival in 19 of the 26 animals used in this study. When these 19 brains were processed for PHA-L immunocytochemistry, 5 of them were found with certainty to have the PHA-L injection confined to the transplant. Based on these cases PHA-L-reactive fibers arising from labelled transplant neurons were traced into the ipsilateral host neocortex adjacent to the transplant and found to project through the subcortical white matter to the ipsilateral parietal neocortical area 1, and claustrum. Callosal fibers were traced to the contralateral frontal neocortical forelimb and parietal areas. Transplant fibers were also observed to descend through the caudate putamen in the dispersed fiber bundles of the internal capsule to distribute as terminal branches and varicose fibers within the mesencephalic periaqueductal gray, red nucleus, deep mesencephalic nucleus, and intermediate gray of the superior colliculus, as well as in the pontine gray. Similar fibers and terminations were present in the caudate putamen, the reticular, ventrobasal, centrolateral, posterior, and parafascicular thalamic nuclei. On the side contralateral to the transplant, fewer fibers were observed in the caudate putamen, the ventrobasal, centrolateral, and posterior thalamic nuclei, as well as more caudally in the deep mesencephalic nucleus and the intermediate gray of the superior colliculus. Our findings demonstrate that homotopic grafts of fetal rat frontal neocortex can project to the developing host brain in a manner which for most projections corresponds to the normal rat neocortical parietal area 1–2 and forelimb area. The density of these transplant-to-host projections is, however, less than in the normal rat corticofugal pathways.
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  • 155
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    Naunyn-Schmiedeberg's archives of pharmacology 346 (1992), S. 588-591 
    ISSN: 1432-1912
    Keywords: Seizures ; Pentylenetetrazol ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A quantitative description of motor seizures induced by pentylenetetrazol (PTZ, metrazol) was performed. Seizures were induced by PTZ in doses from 40 to 120 mg/kg s.c. in 477 male albino rats of the Wistar strain 7 to 90 days old. Two patterns of seizures were elicited: minimal, i.e. predominantly clonic seizures of facial and forelimb muscles with preserved righting ability, and major, i.e. generalized tonic-clonic seizures with a loss of righting reflex. Minimal seizures could be reliably elicited since the age of 18 days; the CD50 for these seizures did not significantly differ with age. Major seizures were elicited regularly at all developmental stages studied. Their CD50 did not significantly differ among 7-, 12- and 25-day-old rat pups but the value for 18-day-old rats was smaller and for adult animals larger than for these three age groups.
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  • 156
    ISSN: 1432-2072
    Keywords: Alcohol withdrawal ; Intoxication ; Seizures ; Aetiology ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male Wistar rats were subjected to repeated weekly episodes of 2 days severe alcohol intoxication (intragastric intubation) and 5 days of withdrawal. In half of the animals the withdrawal reaction was attenuated during the first nine weekly episodes by intragastric intubations with phenobarbital. During episodes 10–14 both phenobarbital treated and phenobarbital untreated animals were allowed to develop a withdrawal reaction; all animals were video-recorded during withdrawal and the records were rated blindly for the occurrence of convulsive seizures. The results were analyzed by stepwise logistic analysis of regression including phenobarbital treatment, alcohol dose and intoxication score as explanatory variables for the occurrence of convulsive seizures. The animals that had been in withdrawal during all episodes developed significantly more convulsive seizures compared with animals that had their first nine withdrawal episodes attenuated by phenobarbital. The development of withdrawal seizures depended on repeated episodes of withdrawal, whereas repeated alcohol intoxication per se did not explain the development of seizures. There were no differences between the groups in the severity of the non-convulsive signs of alcohol withdrawal. Thus the development of seizures and the non-convulsive signs of alcohol withdrawal may result from two pathogenetically different mechanisms: 1) seizures from a cumulative kindling-like effect over long time periods and 2) physical signs of alcohol withdrawal may reflect the degree of physical dependence during the most recent drinking bout.
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  • 157
    ISSN: 1432-2072
    Keywords: Neuroleptics ; Rat ; Field potentials ; Telemetry ; Frequency analysis ; Electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Under the assumption that field potentials recorded from particular brain areas reflect the net balance of neurotransmitter activities, the dose- and time-dependent responses induced by intraperitoneal application of different neuroleptic drugs are quantified by spectral analysis of the electroencephalogram recorded from frontal cortex, hippocampus, striatum and reticular formation. The actions of haloperidol, chlorpromazine, clozapine, prothipendyl and thioridazine in general were characterized by increases of the spectral power in the alpha1 and beta range, at higher dosages also in the theta range. This observed pattern of changes is in line with the neuroleptic induced spectral changes reported in the literature for other animals and man. In the light of the already known effects of other psychoactive drugs on the frequency content of field potentials in the rat, it should now be possible to classify different drugs in terms of their clinical indication. With respect to the type of neurotransmitter control underlying the changes produced by various neuroleptics, it is quite obvious from the comparisons with the respective drug effects that dopamine-D1-receptor controlled transmission is not responsible for this action. On the basis of earlier findings a possible interaction between dopamin-D2 receptor or glutamatergic transmitter control is discussed.
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  • 158
    ISSN: 1432-2072
    Keywords: Neuroleptics ; Remoxipride ; D-2 antagonists ; Sedation ; EEG activity ; Rat ; Rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antipsychotic remoxipride, a selective dopamine D-2 receptor antagonist, was studied for its effects on sleep-waking patterns in the rat and electroencephalographic (EEG) activity in the rabbit. Haloperidol, which has lesser selectivity for D-2 receptors, was used for comparison. In the rat, remoxipride (1–10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep. Only REM was slightly reduced by the high dose of 10 mg/kg. Haloperidol (0.1–1 mg/kg PO) enhanced duration of both total sleep and non-REM sleep. In the rabbit, remoxipride (3 and 10 mg/kg IV) induced no significant changes of the EEG power spectrum over 0.1–38.5 Hz or individual frequency bands. In both cortex and hippocampus the drug did not alter the arousal response to acoustic sensory stimuli. Plasma concentration of remoxipride 10 mg/kg IV in rabbits declined biexponentially and was 4 and 2 µmol/1 at 30 min and 1 h, respectively. Haloperidol (0.3 and 1 mg/kg) slowed down the EEG activity, enhanced the power spectrum of the cortical and hippocampal activity, and significantly reduced the duration of arousal induced by sensory stimuli. The results indicate that, unlike haloperidol, remoxipride has weak or no sedative effects. The data also provide support to the notion that D-2 receptors are not involved in the regulation of states of sleep and sedation.
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  • 159
    ISSN: 1432-2072
    Keywords: CL 218,872 ; Diazepam ; Triazolopyridazine ; Benzodiazepine ; Flumazenil ; Spontaneous locomotion ; Thigmotaxis ; Place learning ; Cue learning ; Morris water maze ; Sedation ; Anxiety ; Amnesia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The sedative, anxiolytic, and amnesic effects of diazepam were compared to those of CL 218,872, a triazolopyridazine that has a preferential affinity for the benzodiazepine ω1 receptor subtype. Spontaneous locomotion was assessed using a running wheel, anxiety was assessed using an open-field divided into central and peripheral areas (thigmotaxis), and amnesia was assessed using the Morris water maze. It was found that CL 218,872, like diazepam, depressed spontaneous locomotion, reduced anxiety, and impaired place learning in a dose-dependent manner. Flumazenil, a benzodiazepine receptor antagonist with a similar affinity for both ω1 and ω2 subtypes, reversed all of the effects of diazepam and antagonized the anxiolytic and amnesic effects, and some but not all of the sedative effects of CL 218,872. These results suggest that the selective activation of the ω1 receptor subtype by CL 218,872 is sufficient to produce sedation, anxiolysis, and amnesia in a manner similar to that produced by the coactivation of both the ω1 and ω2 receptor subtypes with diazepam.
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  • 160
    ISSN: 1432-2072
    Keywords: 5-Hydroxytrytamine ; Lesion ; Operant behaviour ; Temporal differentiation ; IRT〉t schedule ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nineteen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 16 rats received sham injections. The rats underwent 50 daily training sessions under an interresponse-time-greater-than-15-seconds (IRT 〉15 s) schedule of sucrose reinforcement. The lesioned group showed impaired acquisition of temporal differentiation, in that their response rates remained significantly higher and their obtained reinforcement frequencies significantly lower than those of the control (sham-lesioned) group. Comparison of the IRT frequency distributions obtained from the two groups during the last 5 days of training showed that the lesioned group produced a significantly higher proportion of very short IRTs (〈3 s) than the control group; when these short IRTs were disregarded, the lesioned group displayed a significantly lower mean IRT and a significantly higher coefficient of variation than the control group. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results suggest that destruction of the ascending 5HTergic pathways may reduce animals' capacity to inhibit positively reinforced operant behaviour, and may impair temporal discrimination.
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  • 161
    ISSN: 1432-2072
    Keywords: Diazepam ; Idazoxan ; Ipsapirone ; Ritanserin ; Ondansetron ; Acute ; Chronic ; Withdrawal ; Elevated X-maze ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to use the elevated X-maze to compare acute and chronic treatments of a 5-HT1A partial agonist, ipsapirone, a 5-HT2 antagonist, ritanserin, and a 5-HT3 antagonist, ondansetron, with those of established anxiolytic (diazepam) and anxiogenic (idazoxan) compounds. Acute diazepam (5 mg/kg IP) produced a significant increase in the percentage open:total entries and time and time spent in the end of the open arms (anxiolytic profile) on the elevated X-maze. Chronic treatment with diazepam (5 mg/kg IP twice daily for 14 days) still produced an anxiolytic profile which was not apparent 24 h after cessation of chronic treatment (withdrawal). In contrast, idazoxan given both acutely (0.25 mg/kg IP) and chronically (0.8 mg/kg/h at a flow rate of 5.5 µl/h for 14 days, via osmotic minipumps) resulted in a significant decrease in the percentage open:total entries and time and time spent in the end of the open arms (anxiogenic profile). Acute administration of ipsapirone had no effect on any of the behavioural parameters at doses of 0.01 and 1 mg/kg IP, while 0.1 mg/kg IP produced a significant anxiogenic profile. Chronic treatment with ipsapirone (0.01, 0.1 and 1 mg/kg IP twice daily for 14 days) had no significant effect on rat behaviour on the X-maze but 24 h after ending treatment, ipsapirone at the highest dose used (1 mg/kg) produced a significant anxiogenic profile which was absent when the animals were tested 7 days after cessation of treatment. Ritanserin (0.05 and 0.25 mg/kg IP) had no effect acutely on any of the parameters measured but chronic treatment (0.25 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic effect which was still present 24 h but not 7 days after cessation of treatment. Acute ondansetron (0.01, 0.1 and 1 mg/kg IP) had no effect while chronic ondansetron (0.01 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic profile which was not a result of handling during the chronic dosing schedule, an effect was not measureable 24 h after treatment ended. The results demonstrate that the X-maze can detect anxiolytic activity in non-benzodiazepine drugs, as ritanserin and ondansetron showed anxiolytic profiles but only after chronic treatment. In contrast, the X-maze failed to detect any anxiolytic activity with the 5-HT1A partial agonist ipsapirone after either acute or chronic treatment.
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  • 162
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    Psychopharmacology 107 (1992), S. 474-479 
    ISSN: 1432-2072
    Keywords: Flesinoxan ; 5HT1A agonist ; Serotonin ; Antidepressants ; Differential-reinforcement-of-low-rate (DRL) 72-s ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Schedules which selectively reinforce low rates of responding (DRL, differential reinforcement of low rate) distinguish between antidepressants and other types of drugs. In a DRL schedule a subject is required to pause for a specified minimum period of time between two consecutive responses in order to obtain a reinforcer. The dependent variables are rate of responding and rate of reinforcement. Response patterns of rats treated with clinically effective antidepressant drugs such as imipramine (2.0–32.0 mg/kg) or fluvoxamine (4.0–32.0 mg/kg) are characterized by a decrease in response rate and an increase in reinforcement rate. Treatment with the 5-HT1A agonist flesinoxan (0.1–3.0 mg/kg) also dose-dependently decreased response rates while at the same time increasing reinforcement rates. Chlordiazepoxide (2.5–20.0 mg/kg) and diazepam (0.25–2.0 mg/kg) had no effects in the present experiment.d-Amphetamine increased response rates at low doses (0.5–2.0 mg/kg), and decreased it at the higher doses (4.0 mg/kg), but reinforcement rates were unaltered. Overall analysis of the effects of haloperidol (0.02–0.32 mg/kg) showed decreased responding and increased reinforcement rates. Post hoc analysis, however, clearly differentiated between haloperidol's profile and that of the antidepressants. As such, the results of the present experiment show that flesinoxan might possess antidepressant activity in humans.
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  • 163
    ISSN: 1432-2072
    Keywords: Conditioned avoidance response ; 8-OH-DPAT ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 8-OH-DPAT, a selective 5-HT1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.
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  • 164
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    Psychopharmacology 109 (1992), S. 145-152 
    ISSN: 1432-2072
    Keywords: Methylphenidate ; Response rate ; Reinforcement efficacy ; Motor performance ; Matching law ; Response strength equation ; Rate dependency principle ; Clinical effects ; Variable-interval schedule ; Lever press ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This experiment evaluated the effects of methylphenidate on reinforced responding in rats. In each session the subjects (rats) earned reinforcement on seven different variable-interval reinforcement schedules. The average intervals varied from 108 to 3 s and provided reinforcement rates ranging from about 30 to 1100/h. Response rate was a negatively accelerated function of reinforcement rate. Low doses of methylphenidate (1.0 and 2.0 mg/kg) increased responding maintained by the four leanest schedules, but had little effect on responding maintained by the three densest schedules. In contrast, an 8.0 mg/kg dose increased responding maintained by the three densest schedules and slightly decreased responding maintained by leaner schedules. A quantitative model of reinforced responding, referred to as the matching law or response strength equation, was fitted to the data. This equation has two parameters. On the basis of previous experiments, one was used to measure changes in reinforcement efficacy and the other was used to measure changes in motor performance. The 1.0 and 2.0 mg/kg doses changed the reinforcement parameter in the same way as did increases in deprivation and reward magnitude. The 8.0 mg/kg dose changed the motor parameter in the same was as did decreases in lever weight. It was concluded that methylphenidate increases reinforcement efficacy, and that the highest dose changed the topography of responding. The results are discussed in terms of the response strength equation, the rate dependency principle, and the question of how to interpret changes in reinforcement efficacy and motor performance.
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  • 165
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    Psychopharmacology 109 (1992), S. 177-184 
    ISSN: 1432-2072
    Keywords: Dietary self-selection ; Corticotropin-releasing factor ; α-Helical CRF9–41 ; Chlordiazepoxide ; Neophilia ; Protein ; Rat ; Restraint stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 µg ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist,α-helical CRF9–41 (1, 5 and 25 µg ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 µg) reversed the anorexia produced by CRF (0.5 µg) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.
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  • 166
    ISSN: 1432-2072
    Keywords: Alcohol intake ; Development ; Ethanolamine O-sulphate ; GABAA receptors ; Postnatal ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Long-term effects of chronic treatment with a GABA-T (GABA-transaminase) inhibitor, ethanolamine O-sulphate (EOS) (200 mg/kg/day for the postnatal days 3–21) on the binding parameters of GABAA receptors, hypothalamic monoamines and subsequent behavior were studied in Wistar rats. At the age of 1 month, EOS-treated rats showed reduced activity in the open-field and, at the age of 4 months, their voluntary alcohol consumption was increased. No changes were seen in Porsolt's swim test or in the plus-maze test. Weight gain was significantly retarded in EOS-treated rats. Maximal stimulation of [3H] flunitrazepam binding by GABA was decreased in the cerebral cortex and the EC50-value for the GABA stimulation increased in the hippocampus in the EOS rats at the age of 4 months. EOS treatment did not alter the cerebellar diazepam sensitive and insensitive binding components of the imidazobenzodiazepine [3H]Ro 15-4513. No changes were observed in the hypothalamic monoamine concentrations. The results are in agreement with the idea that GABA-T inhibitor treatment permanently alters GABAA mechanisms. Moreover, altering the CNS GABA level during development increases adult alcohol intake in rat.
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  • 167
    ISSN: 1432-2072
    Keywords: Methamphetamine ; Rat ; Behavior ; Ocular effects ; Organogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Gravid Sprague-Dawley CD (VAF) rats received 50 mg/kg (d,l)-methamphetamine (MA) HCl (expressed as free base,N=15) or distilled water (N=6) by SC injection × 2/day in a 3 ml/kg volume on embryonic (E) days 7–12. Control rats were pair-fed to MA-exposed dams on days E7–18. No control dams failed to deliver; however, of 15 MA-exposed dams 4 did not deliver (2 died and 2 had completely resorbed litters). One additional MA litter had all the offspring die shortly after birth. There was no difference between groups on offspring postnatal (P) body weight. The offspring exposed prenatally to MA had significantly lower olfactory orientation scores (P9, 11, 13) to their home cage scent. In a test of early activity (P10, 12, 14) the MA-exposed progeny were marginally less active than controls. MA-exposed offspring exhibited hyperreactivity and marginally shortened response latency on a test of acoustic startle (P27). Motor activity showed no differential response in MA treated or control offspring to MA (P63) or fluoxetine challenge (P70). However, the MA offspring were more active than controls with respect to central and side activity during the second week of testing. No group differences were found for performance in a straight swimming channel or on the number of errors committed or latency to escape in a complex (Cincinnati) water maze (P84). Prenatal exposure to MA also induced eye defects (i.e., anophthalmia, microphthalmia and folded retina) in 16.7% of the progeny. However, MA did not effect hippocampal or neostriatal monoamine levels when measured on P28. These data support the hypothesis that MA is behaviorally and ocularly teratogenic to the developing rat and results in functional deficits when compared to offspring of pair-fed controls.
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  • 168
    ISSN: 1432-2072
    Keywords: Neurotensin ; Dopamine ; Mesolimbic system ; Antidepressant activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Locomotor activity and behaviour in the forced swimming test were examined in rats which had received neurotensin (0.5–5.0 µg) in the ventral tegmental area. Doses of 5 µg neurotensin but not lower increased the locomotor activity for at least 2 h. At 0.5 and 1.0 µg neurotensin significantly increased the time the animals spent in struggling with no changes in general motor activity (swimming). The effect of 1.0 µg neurotensin on struggling was completely antagonized by 0.5 µg (−)-sulpiride administered in the posterior nucleus accumbens. The results suggest that activation of the mesolimbic dopamine system through administration of neurotensin in the ventral tegmental area produces antidepressant-like effects. The significance of these findings for a role of endogenous neurotensin in depression remains to be clarified.
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  • 169
    ISSN: 1432-2072
    Keywords: Cholinergic system ; Scopolamine ; Hippocampus ; Spatial discrimination ; Learning ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The involvement of hippocampal cholinergic synapses in spatial discrimination learning was evaluated by locally administering scopolamine into the hippocampus. Sixteen 16-month-old male Lewis rats received bilaterally implanted cannulae aimed at the dorsal part of the hippocampus. The rats were trained on a repeated acquisition test in the Morris water-escape task. In this procedure the invisible platform is randomly moved from day to day to one of four possible locations. Thus, the rat has to learn to localize the platform from day to day. On each day the rats received four pairs of trials. Scopolamine injections (35 µg in 1 μl per hippocampus) were given to one group (n=8) on days 5 and 7. On days 6 and 8 all rats received saline injections. Place learning was retarded in the scopolamine-treated rats during the first swims of pairs of trials. During second swims the scopolamine-treated rats showed a general performance deficit, indicating that first and second swims were differentially affected. The data support the hypothesis that cholinergic neurotransmission in the dorsal hippocampus is involved in spatial learning processes.
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  • 170
    ISSN: 1432-2072
    Keywords: Footshock ; Stress ; Behaviour ; Diazepam ; Flesinoxan ; Fluvoxamine ; Desmethylimipramine ; Anxiety ; Depression ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the “noise test” 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0–30.0 mg/kg) and desmethylimipramine (DMI, 2.5–10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with flvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6–5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3–3.0 mg/kg). Both acute and chronic drug treatment were equally effective in reversing the shock-induced locomotion deficits as well as the marked immobility response in S rats, although rearing was not reversed. However, flesinoxan also increased locomotion and reduced rearing in C rats, suggesting some nonspecific stimulating effects of flesinoxan. In conclusion, the footshock-induced long-lasting behavioural changes are sensitive to treatment with (putative) anxiolytic agents, whereas no beneficial effect of the antidepressant drugs was found.
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  • 171
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    Psychopharmacology 109 (1992), S. 403-409 
    ISSN: 1432-2072
    Keywords: Dopamine ; D1 ; D2 ; SKF 38393 ; SKF 77434 ; SKF 82958 ; SCH 23390 ; Spiperone ; Feeding ; Behavior ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A series of experiments was conducted to examine the effects of dopamine D1 receptor agonists on food intake in rats. In the first experiment, the D1 agonist SKF 38393 (3.0–30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D1 agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 〉 SKF 77434 〉 SKF 38393 (ED50 values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D1 antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1–10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D1 antagonist. The effects of SKF 82958 were also antagonized by the D2 receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D1 receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D1 receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D1 agonist. The results also demonstrate the need for comparisons among several compounds in studies of D1 mediated behavioral effects.
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  • 172
    ISSN: 1432-2072
    Keywords: SCH 23390 ; SCH 39166 ; D1 dopamine receptor ; Antagonist ; Pharmacokinetics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A gas chromatographic method for measuring concentrations of a novel D1 antagonist SCH 39166 [(−)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5-H-benzo[d]naphto(2,1–6)azepine] in rat brain and plasma was developed. The method was applied to descriptive pharmacokinetics of two subcutaneous doses of SCH 39166 (0.25 mg/kg and 2.5 mg/kg). For comparison, concentrations of the “prototype” D1 antagonist SCH 23390 (0.25 mg/kg, SC) [R-(+)-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine] were also measured in plasma and brain. SCH 23390 (0.25 mg/kg, SC) had a very short elimination half-life of about 30 min in plasma, and disappeared in a slightly slower manner from striatum and cortex. SCH 39166 (0.25 and 2.5 mg/kg, SC), however, had a longer elimination half-life of about 1.5–2.5 h in plasma and brain. Interestingly, the 2.5 mg/kg dose of SCH 39166 produced only two-to five-fold increases in maximum concentrations in plasma and brain compared to the 0.25 mg/kg dose. The reason for this is not clear. The ability of these two doses of SCH 39166 to induce catalepsy in the bar test was also evaluated. It was found that SCH 39166 in these two doses, unlike SCH 23390, was not cataleptic. In conclusion, these pharmacokinetic features of SCH 39166 in the rat should be useful when designing experiments with this novel selective D1 antagonist. Furthermore, the longer elimination half-life of SCH 39166 makes it a more useful probe in pharmacodynamic comparisons of D1 receptor antagonists and classical as well as atypical neuroleptics.
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  • 173
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    Psychopharmacology 107 (1992), S. 457-460 
    ISSN: 1432-2072
    Keywords: Defense ; Submission ; Flight ; Ethopharmacology ; Pentylenetetrazol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In a previous work, using the resident-intruder situation, we have shown that a benzodiazepine inverse agonist could exert a “fear-promoting” effect, in decreasing self-defensive behaviours while increasing submissive postures. To further test this hypothesis, the effects of pentylenetetrazol on different forms of defensive behaviour were examined in male intruder rats confronted with offensive residents. Administration of pentylenetetrazol (10 and 20 mg/kg, IP) increased submissive postures such as immobility and on-the-back, but reduced self-defensive postures. Other active behaviours were not reduced, thus excluding a non-specific behavioural suppression. These results suggest that self-defensive and submissive behaviours can be dissociated and that anxiogenic compounds are more likely to increase submissive behaviours than self-defensive ones.
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  • 174
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    Psychopharmacology 108 (1992), S. 40-46 
    ISSN: 1432-2072
    Keywords: Physical dependence ; Acoustic startle response ; Withdrawal ; Morphine ; Naloxone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A series of experiments was conducted to assess the sensitivity of the acoustic startle response to chronic morphine administration and naloxone-precipitated withdrawal. Rats were implanted with two subcutaneous pellets containing either 75 mg each of morphine or containing only placebo. In experiment 1, withdrawal induced by 0.05–0.2 mg/kg naloxone dose-dependently decreased the magnitude of the startle response. Physical dependence was confirmed by a naloxone-induced acute weight loss seen in morphine-implanted rats, but naloxone had no effect on startle or body weight in nondependent animals. In experiment 2, a modified procedure with fewer trials per session and fewer test days was employed. Naloxone (0.2 mg/kg) given 4–5 days after implantation induced large startle-response decreases in morphine-dependent rats while having no effect in placebo-implanted rats. Post-naloxone saline tests revealed no significant differences in startle between morphine and placebo groups. Startle scores were significantly higher in morphine-implanted rats than in placebo rats during a saline test given 3 days following pellet implantation. In a separate group of animals, however, acute IP injections of morphine from 0.3–10 mg/kg had no significant effect on startle amplitude. The effect of repeated pairings of withdrawal with the startle environment was assessed in experiment 3. Morphine-dependent rats startled significantly less if naloxone injections were given before the startle session than if they were administered 4 h later. Conditioned withdrawal effects, expressed during a final test session when all rats received saline, were observed for the body-weight measure but not for the startle response. These results suggest that the acoustic startle response may be a useful objective measure in evaluating physical dependence produced by substances of abuse.
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  • 175
    ISSN: 1432-2072
    Keywords: Yawning ; Penile erections ; (+) S-20499 ; 5-HT1A agonists ; D2 receptors ; Apomorphine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4–5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10−8 M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 µg/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2–5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.
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  • 176
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    Psychopharmacology 108 (1992), S. 147-152 
    ISSN: 1432-2072
    Keywords: Diazepam ; Morphine ; Naloxone ; Flumazenil ; Place learning ; Cue learning ; Morris water maze ; Benzodiazepines ; Opioids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.
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  • 177
    ISSN: 1432-2072
    Keywords: Conflict schedule ; FG 7142 ; Inverse agonist ; Punishment ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous work (Thomas et al. 1990) showed that an anxiolytic benzodiazepine increased the time allocated to responding in a conflict situation (where responses were both food-reinforced and shock-punished) versus a nonpunishment situation. The present experiment tested whether a benzodiazepine-receptor inverse agonist (FG 7142, 1–30 mg/kg) would have the opposite effect (i.e., decrease time spent responding in a punishment situation). Chain pulls determined whether a rat's lever presses were reinforced on 1) a lean variable-interval schedule, or 2) a richer variable-interval schedule in which responding also produced shock intermittently. FG 7142 dose-dependently decreased nonpunished lever responding, but did not affect punished responding. The drug nonselectively decreased chain pulling (the schedule-switching response). Like chlordiazepoxide, FG 7142 increased the time spent in the punishment component, showing that not all effects of benzodiazepine-receptor agonists and inverse agonists are opposite. These results are inconsistent with expectations that anxiogenic actions of FG 7142 should 1) decrease punished responding; 2) increase the rate of responses that terminate the punishment condition; and 3) decrease time spent in the punishment component. Rather, nonsuppressed responding seems most sensitive to decreases by FG 7142.
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  • 178
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    Psychopharmacology 108 (1992), S. 229-234 
    ISSN: 1432-2072
    Keywords: Anxiolysis ; Benzodiazepine agonist, midazolam ; Benzodiazepine antagonist, flumazenil ; α2-Adrenergic agonists, dexmedetomidine ; α-Adrenergic antagonists, atipamezole ; α1-Adrenergic antagonists, prazosin ; Elevated plus-maze ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The anxiolytic profile of dexmedetomidine, a novel, highly-selective α2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1–10 µg/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1–10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 µg/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an α2-adrenergic antagonist, atipamezole, 10–50 µg/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the α1-adrenergic antagonist, prazosin, 0.1–10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and α2-agonist responses do not share any molecular component, there does appear to be “crosstalk” between these two systems. These may involve GABA or noradrenergic “downstream” effects of either dexmedetomidine or midazolam, respectively.
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  • 179
    ISSN: 1432-2072
    Keywords: Sleep-wakefulness ; Chronic cocaine treatment ; Cocaine discontinuation ; Ritanserin ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of ritanserin, a 5-hydroxytryptamine-2 (5-HT2) receptor antagonist, and chlordiazepoxide, a benzodiazepine agonist, on sleep-wakefulness disturbances in rats after acute administration of cocaine and after discontinuation of chronic cocaine treatment were examined. Intraperitoneal (IP) injection of chlordiazepoxide (10 mg/kg) but not ritanserin (0.63 mg/kg) prevented the increase of wakefulness (W) and the reduction of light slow wave sleep (SWS1) and deep slow wave sleep (SWS2) induced by an acute injection of cocaine (20 mg/kg IP). Daily injection of cocaine (20 mg/kg for 5 days, then 30 mg/kg for 5 days IP) at the onset of the light phase elicited an increase of W and a concomitant decrease of SWS1, SWS2 and paradoxical sleep (PS) in the light phase, followed by a rebound in SWS2 and PS in the subsequent dark phase. Following cocaine discontinuation, the circadian distribution of sleep-wakefulness states remained disturbed in saline-treated rats for at least 5 days. Both ritanserin (0.63 mg/kg IP/day) and chlordiazepoxide (10 mg/kg IP/day) reduced the alteration in the distribution of W and SWS2 throughout the light-dark cycle from the first day of administration on, but failed to prevent PS alterations. The mechanisms by which both compounds exert their effect are probably quite different. For chlordiazepoxide sedative and sleep-inducing properties probably play a major role. In contrast, for ritanserin SWS2-increasing properties and its ability to reverse preference for drugs of abuse without inducing aversion might be key factors.
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  • 180
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    Psychopharmacology 108 (1992), S. 283-288 
    ISSN: 1432-2072
    Keywords: Clonidine ; UK-14.304 ; Behaviour ; Withdrawal ; Doxazosine ; Morphine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Opiate withdrawal is associated with behavioural symptoms and a sympathetic hyperactivity, the latter being sensitive to clonidine. The central question is whether behavioural symptoms would be also sensitive to clonidine. A rat model was used in which the locomotor activity was measured 24 h a day during the morphine withdrawal phase. Spontaneous withdrawal of morphine reduced strongly the high nocturnal locomotor activity, concomitently decreasing food intake and body weight. Chronic infusion of clonidine (30–120 µg/kg/day) using osmotic minipumps had no effect on the withdrawal symptoms. Higher dosages (250–1000 µg/kg/day) potentiated rather than alleviated the withdrawal symptoms, suggesting anα 1-adrenergic effect of clonidine rather than anα 2-action. Therefore, we studied the action of a more specificα 2-agonist UK-14.304. UK-14.304 was less potent than clonidine in naive animals. It slightly alleviates the decrease of nocturnal activity during spontaneous morphine withdrawal. Furthermore, we have tested whether the effects of high dosages of clonidine could be altered by a specificα 1-antagonist doxazosine. Doxazosine reduced only slightly the potentiation in the decrease in food intake by clonidine during morphine withdrawal. For the other symptoms no interaction between doxazosine and clonidine was found. The data suggest that the use of clonidine in the detoxification of opiate dependent people is based on the suppression of the sympathetic hyperactivity rather than on symptoms with a more behavioural character.
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  • 181
    ISSN: 1432-2072
    Keywords: Short-term memory ; Aging ; Noradrenergic system ; Alpha-2 adrenoceptors ; Cholinergic system ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study investigated the effects of dexmedetomidine (an alpha-2 adrenoceptor agonist), atipamezole (an alpha-2 adrenoceptor antagonist) and tacrine (an inhibitor of acetylcholinesterase) on the performance of adult and aged rats in a delayed non-matching to position task assessing spatial short-term memory. Most of the aged rats were impaired in the pretraining phases and in the acquisition of the non-delayed version of the task. After a substantial training period of the delayed version of the task, both adult and aged rats reached their asymptotic level of performance. Both adult and aged rats showed a decline in the percent correct responses at the longest delays in this task, and a delay independent decrease in the percent correct responses across the delays (0–30 s) was found in the group of aged rats (25-month-old) as compared to the adults (10-month-old). Dexmedetomidine (0.3, 1.0 or 3.0 µg/kg), atipamezole (0.03, 0.3 or 3.0 mg/kg) and tacrine (1.0 or 3.0 mg/kg) did not increase the percent correct responses in adult or aged rats. The highest doses of dexmedetomidine and tacrine decreased behavioural activity of rats during this short-term memory testing. Atipamezole (0.03 mg/kg) increased behavioural activity of rats. The results suggest that acute, systemic administrations of alpha-2 drugs or an anticholinesterase do not improve short-term memory in rats.
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  • 182
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    Pflügers Archiv 420 (1992), S. 342-346 
    ISSN: 1432-2013
    Keywords: Patch-clamp ; Rat ; Olfactory receptor neurons ; Sodium channels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Na+ currents were observed in acutely-dissociated adult rat olfactory receptor neurons using the whole-cell recording techniques. The threshold for current activation was near −70mV and currents were fully activated by −10 mV (midpoint: −45 mV). Steady-state inactivation was complete at potentials more positive than −70mV and half complete at −110mV (±〈1, n=8). Complete recovery from inactivation required one second at −100 mV (n=7). The addition of 10 μM tetrodotoxin or 1 mM Zn2+ to the external solution was required to completely block the current. The current differs from those in amphibian and cultured neonatal rat olfactory neurons in its unusually negative voltage-dependence and slow recovery. Since mammalian olfactory neurons have very high input resistances, physiological resting potentials cannot usually be measured using whole-cell recording techniques. However, predominantly-capacitatively-coupled spikes activated by depolarisation were frequently observed in cell-attached patches. This indicates that the cells were excitable and implies that they must have had resting potentials more negative than −90 mV in order for this current to underlie the action potential.
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  • 183
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    Pflügers Archiv 422 (1992), S. 267-272 
    ISSN: 1432-2013
    Keywords: Rat ; Myoball ; Potassium channel ; Potassium current ; Sodium current ; Insulin ; Voltage clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A whole-cell early transient outward current occurs in rat myoballs if and only if there is an immediatly preceding current of large amplitude through the voltage-gated, tetrodotoxin-inhibitable Na+ channel. This early outward transient is a K+ current, designated I K(Na+). Under the conditions in which I K(Na+) appears, simultaneous measurement of voltage and current, under voltage clamp, demonstrates that there is transient voltage escape to depolarized levels, peaking at about the time of peak inward Na+ current arid resembling an action potential. I K(Na+) was never seen in the absence of this breach of the voltage clamp, suggesting that I K(Na+) might be an artefact due to transient depolarization from the clamp. However, when the voltage escape was mimicked by voltage commands under conditions in which the Na+ channel was not activated, there was no I K(Na). Insulin increased or produced I K(Na+) even though insulin had no effect on I Na or on the delayed rectifier K+ current or on the escape from voltage clamp. It is concluded that there is a population of rat myoballs in which there is an early outward K+ current that requires an immediately preceding current through the voltagegated tetrodotoxin-inhibitable Na+ channel and is enhanced by insulin.
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  • 184
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    Archives of gynecology and obstetrics 252 (1992), S. 73-80 
    ISSN: 1432-0711
    Keywords: Uterine-surgery ; Rat ; Intestinal-surgery ; Fertility-surgery ; Intestinal secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A one centimeter length of the left uterine horn in two groups of Wistar rats (n=10) was replaced with normal (VAS group) or with denervated and devascularizated (NVAS group) colonic grafts. All animals maintained pregnancy in the right control horns but not in the grafted horns. At 40, 60 and 90 days after surgery, the light microscopic appearance of the autografts was studied. In the VAS group, and with respect to the last period, the number (5.5±0.7) and height (1.0±0.1 mm,P〈0.05 ANOVA) of the folds, the intestinal glands height (160.2±21.2μ,P〈0.05 ANOVA) and the number of globet cells per gland (26.6±4.2,P〈0.05 ANOVA) had decreased in relation to the colon control (6.0±0.7, 1.4±0.1, 251.7±31.8, 42.6±5.2 respectively). A similar intestinal structure to that described above was observed in the anastomosis areas of the NVAS group, and therefore a decreased mucus production was maintained in this areas. No folds or intestinal glands were observed, but a monoestratified cubic epithelial cells type was observed along 63.7±4.1% of the NVAS colonic graft center. Under this epithelium a connective tissue, like a non-glandular submucosa, was obtained.
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  • 185
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    Archives of toxicology 66 (1992), S. 700-705 
    ISSN: 1432-0738
    Keywords: Aluminum ; Toxicokinetics ; Rat ; Parenterals
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The toxicokinetics of aluminum (Al) in male Wistar rats was studied after single intragastric (IG) doses of 1000 and 12000 μg Al/kg and intravenous (IV) doses of 10, 100, 1000, and 12000 μg Al/kg. Serial blood samples, daily samples of urine and feces as well as brain, liver, kidney, spleen, quadriceps muscle, and femur samples were collected. Al was measured by atomic absorption spectrometry. Al blood profiles after IV doses were adequately described by a two-compartment open model. Al toxicokinetics was dose dependent and appeared to plateau at 12000 μg/kg. At IV doses between 10 and 1000 μg/kg the terminal half-life of elimination from whole blood (t1/2β) increased from 29.9±7.8 to 209.3±32.6 min, and the total body clearance (CL) decreased from 2.45±0.64 to 0.28±0.03 ml min−1 kg−1. Following an IV bolus of 10 and 100 μg/kg the administered Al was recovered completely from urine (94.4%±9.9% and 98.5%±3.2%). Twenty-nine days after the IV dose of 1000 μg/kg daily renal excretion decreased to baseline values while only 55.1%±8.0% of the dose was excreted. Nineteen days after the single IV dose of 1000 μg/kg Al accumulated in liver (28.1±7.7 versus 1.7±0.5 μg/g of control rats) and spleen (72.5±21.1 versus 〈0.4 μg/g). After the single 1000 μg/kg IG dose no absorption of Al was detectable. The IG dose of 12000 μg/kg resulted in a maximum blood Al level of 47.9±12.4 μg/l after 50 min. The blood concentration time curve fitted a one-compartment open model with a half-life of absorption of 28.2±3.6 min and a t1/2β of 81.2±20.2 min. Cumulative renal Al excretion was 0.18%±0.10% of the dose and oral bioavailability was 0.02%. Seventeen days after the 12000 μg/kg IG dose the Al content in femur samples was increased (2.7±1.3 versus 0.6±0.4 μg/g). In no case was fecal elimination of incorporated Al observed.
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  • 186
    ISSN: 1432-0738
    Keywords: N-Nitrosamine ; Cytochrome P-450 ; Rat ; Phenobarbital ; β-Naphthoflavone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Five cytochrome P-450 forms were purified from livers of rats pretreated with phenobarbital (PB) or β-naphthoflavone (BNF), and the oxidative dealkylation of N-nitrosodialkylamines by the reconstituted cytochrome P-450 systems was measured. PB-II (P450IIB1) showed very high N-nitrosomethybutylamine (NMBA) debutylase activity, high NMBA demethylase activity and high N-nitrosomethyl-benzylamine (NMBeA) debenzylase activity, suggesting that the increase following PB treatment in hepatic microsomal NMBA debutylation and NMBeA debenzylation was due to the induction of PB-II. BNF-H (P450IA2) showed very high NMBA debutylase and high NMBeA debenzylase activities, and BNF-L (P450IA1) showed NMBA debutylase and high NMBeA debenzylase activities. These results suggested that the increase by BNF pretreatment in hepatic microsomal NMBA debutylation was due mainly to the induction of BNF-H and in some part to that of BNF-L. PB-II also showed very high dealkylation activity of lipophilic N-nitrosodialkylamines with long alkyl moieties. On the other hand, BNF-H dealkylated N-nitrosodipropylamine (NDPA), N-nitrosomethylbutylamine (NMBA) and N-nitrosoethylbutylamine (NEBA) at higher rates than N-nitrosodibutylamine (NDBA). BNF-L dealkylated NEBA at higher rates than NMBeA and NDBA. These results reveal that substrate specificity of each cytochrome P-450 form in N-nitrosodialkylamine metabolism is different from each other and several forms of cytochrome P-450 support each N-nitrosamine dealkylase activity in mammalians.
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  • 187
    ISSN: 1432-0738
    Keywords: Ethoxyquin(6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) ; Nephrotoxicity ; Rat ; Proteinuria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The toxicity of ethoxyquin (EQ) to rat kidney was examined in males which were either weanling or adult at the beginning of the experiment, and also in adult females. Female rats were much less susceptible to the toxic effects of EQ than males of the same age. In males damage to the cortex, mainly as an acceleration of the normal ageing process, was similar in both age groups, but rats exposed to EQ as weanlings also suffered from extensive papillary necrosis. Male rats were more prone than females to proteinuria, which was greatly exacerbated by EQ in both age groups. Thus there is very little evidence of nephrotoxicity in adult female rats on exposure to EQ at 0.5% in the diet for 26 weeks. In males, the initial age of the animal, as well as the length of treatment, influences the extent of damage.
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    Archives of toxicology 66 (1992), S. 279-285 
    ISSN: 1432-0738
    Keywords: Acetaminophen ; Aminophenazone ; Ammonium metavanadate ; Brain ; Buthionine sulfoximine ; Cobalt ; Diethylmaleate ; Glutathione ; Lomustine ; Morphine ; Mouse ; Nitrofurantoin ; Phenytoin ; Propyphenazone ; Rat ; Starvation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since glutathione is thought to be involved in cerebral functions, changes in the glutathione level imply modulations of the neurotransmission in addition to all the known effects of GSH. It was investigated whether alterations of the cerebral glutathione can be induced by consumption of GSH, by inhibition or stimulation of the synthesis of GSH, or by an inhibition of the re-reduction of the oxidized glutathione. Aminophenazone, propyphenazone, acetaminophen, phenytoin, morphine and nitrofurantoin, known to deplete hepatic GSH, had no effects on cerebral GSH. Diethyl maleate (0.6 ml/kg) decreased the cerebral content of GSH and GSSG in adult rats as well as in fetuses. The depletion of the cerebral GSH caused by diethyl maleate treatment for 4 days was followed by an increase up to 125% and a subsequent return to the normal level after 1 week. In rats starved up to 71 h deficiency of exogenous amino acids caused only a minimal or no decrease in cerebral GSH. The specific inhibitor of the gamma-glutamylcysteine synthetase BSO only depleted GSH in the brain of young mice following the repeated s. c. administration of a high dose (890 mg/kg). After cobaltous chloride (20 mg/kg; twice a day for 2 or 4 days) the GSH level in the brain was unchanged. In vivo inhibition of the cerebral glutathione reductase was caused by ammonium metavanadate (12.5 mg/kg; three times a week for 6 weeks). Nitrofurantoin (150 mg/kg) had no effect. After lomustine (10 mg/kg) a minimal increase in glutathione reductase was found, but simultaneously also an increase in GSSG and of the ratio GSSG/total glutathione.
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    Archives of toxicology 66 (1992), S. 315-320 
    ISSN: 1432-0738
    Keywords: Cadmium ; Rat ; Bone ; Long-term administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A decrease in mechanical strength of bones was observed both in young and old rats for long periods of administration of cadmium. Young (3-week-old) female rats were given 0 (control), 5 and 10 ppm cadmium in drinking water, respectively, for 20 weeks. Old (18-month old) female rats were given 0 (control) and 40 ppm cadmium in drinking water, respectively, for 7 months. The compression strengths of bones of young rats which were given 10 ppm cadmium, and those of old rats which were given 40 ppm cadmium, significantly decreased at the distal end portion of femur. Cadmium contents in bones in the 10 ppm and 40 ppm groups were about 110 and 210 ng/g dry weight, respectively. The present result confirmed that cadmium has a lesional effect on the mechanical strength of bone at the concentration of 100–200 ng/g in dry weight of bone, for both young and old rats.
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  • 190
    ISSN: 1432-0738
    Keywords: Toxicology ; Poisoning ; Toluene ; Brain regional distribution ; Rat ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Toluene concentrations in 9 brain regions of acutely exposed rats and that in 11 brain regions of a human case who inhaled toluene prior to death are described. After exposure to toluene by inhalation (2000 or 10000 ppm) for 0.5 h or by oral dosing (400 mg/kg), rats were killed by decapitation 0.5 and 4 h after onset of inhalation and 2 and 10 h after oral ingestion. After each experimental condition the highest range of brain region/blood toluene concentration ratio (BBCR) was in the brain stem regions (2.85–3.22) such as the pons and medulla oblongata, the middle range (1.77–2.12) in the midbrain, thalamus, caudate-putamen, hypothalamus and cerebellum, and the lowest range (1.22–1.64) in the hippocampus and cerebral cortex. These distribution patterns were quite constant. Toluene concentration in various brain regions were unevenly distributed and directly related blood levels. In a human case who had inhaled toluene vapor, the distribution among brain regions was relatively similar to that in rats, the highest concentration ratios being in the corpus callosum (BBCR: 2.66) and the lowest in the hippocampus (BBCR: 1.47)
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  • 191
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    Archives of toxicology 66 (1992), S. 496-502 
    ISSN: 1432-0738
    Keywords: Spontaneous ; Tumor ; Neoplasm ; Rodent ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Incidence of neoplastic lesions in untreated Sprague-Dawley rats (1340 males and 1329 females) used as controls in 17 carcinogenicity studies are tabulated and evaluated. In male rats, the most common neoplasms were benign pheochromocytomas and keratoacanthomas (4.0% in each case) followed by pancreatic islet cell adenomas (3.7%), thyroid parafollicular cell adenomas (3.6%), fibromas and squamous cell papillomas of the skin and hepatocellular adenomas (2.0% in each), malignant lymphoma lymphocytic (1.9%), histiocytic sarcomas (1.4%), and adrenal cortical adenomas (1.2%). In female rats, the most common neoplasms were of mammary gland origin (31.3%: fibroadenoma 19.0%, adenocarcinomas 8.8%, and adenomas 3.5%) followed by thyroid parafollicular cell adenomas (2.9%), uterine endometrial stromal polyps (2.6%), adrenal cortical adenomas (1.9%), malignant lymphoma lymphocytic (1.6%), fibromas in the skin (1.3%), and pancreatic islet cell adenoma (1.1%). Metastases were observed from pheochromocytomas, hepatocellular carcinomas, nephroblastomas, renal pelvis transitional cell carcinoma, interstitial cell tumor and seminoma of the testes, Zymbal's gland adenocarcinomas, and mammary adenocarcinomas.
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  • 192
    ISSN: 1432-0738
    Keywords: Pyridoxine ; Vitamin B6 ; Testis ; Reproductive system ; Spermatogenesis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Although it has been indicated that many neurotoxicants also cause reproductive toxicity, the reproductive toxicity of megadoses of pyridoxine, which is a neurotoxicant, has not been studied. In this paper, we studied the effects of megadoses of pyridoxine on male reproductive organs. Pyridoxine hydrochloride, 125 mg/kg, 250 mg/kg, 500 mg/kg or 1000 mg/kg, daily, was intraperitoneally injected into Wistar male rats 5 days a week for 2 or 6 weeks, and its effects on the male reproductive organs were investigated. After 2 weeks of administration, absolute weights of the testis in the 500 and 1000 mg/kg epididymis in all the exposed groups and prostate gland in the 1000 mg/kg group decreased, and mature spermatid counts in the testis decreased in the 1000 mg/kg group. After 6 weeks administration, the absolute and relative weights of the testis, epididymis, prostate gland and seminal vesicle decreased in the 500 mg/kg and 1000 mg/kg groups, and mature spermatid counts in the testis and sperm counts in the epididymis decreased in these groups. Among the marker enzymes of the testicular cells, LDH-X activity decreased, and β-glucuronidase activity, cytochrome P-450 content and cytochrome b5 content increased in the 1000 mg/kg group. Plasma testosterone concentration did not significantly alter in all the exposed groups. From these results, it was concluded that megadoses of pyridoxine affected the spermatogenesis and decreased reproductive organ weights in the rat.
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  • 193
    ISSN: 1432-0738
    Keywords: Inhalation ; Mouse ; Pharmacokinetic model ; physiologically-based, two-compartment ; Rat ; Acetone ; 1,3-Butadiene ; 2-Butanone ; 1,1-Dichloroethylene ; 1,1-Difluoroethylene ; 1,2-Epoxybutene-3 ; Ethylbenzene ; Ethylene oxide ; n-Hexane ; Isobutene ; Isoprene ; 2-Nitropropane ; Toluene ; 1,1,1-Trichloroethane ; 1,1,2-Trichloroethane ; Styrene ; m-Xylene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experimental data obtained in vivo with the closed-chamber gas uptake technique have been reported for a series of volatile chemicals. Pharmacokinetic analyses of these data have been performed either by using a two-compartment model or physiological models. In the former the transfer rate of chemical from ambient air to body is defined by the clearance of uptake. In the latter models the transfer rate depends on alveolar ventilation, cardiac output, and blood: air partition coefficient. In this communication we describe the quantitative relationship between clearance of uptake and alveolar ventilation, cardiac output, and blood: air partition coefficient. Theoretical values of clearance of uptake were calculated for a variety of volatile chemicals using literature data on alveolar ventilation, cardiac output, and blood: air partition coefficient. For most chemicals the experimentally determined values in rats and mice were about 60% of the theoretical values. This suggests that the inhalatory uptake rate of chemical may be overestimated if literature values of alveolar ventilation are used in physiological pharmacokinetic models for rodents.
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  • 194
    ISSN: 1432-0738
    Keywords: Bezafibrate ; Rat ; Strain differences ; Lipids ; Marker enzymes ; Peroxisomes ; Mitochondria ; Micro-somes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal Β-oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid Β-oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.
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  • 195
    ISSN: 1432-0738
    Keywords: Kidney ; Liver ; Cell proliferation ; Rat ; Mouse ; p-Dichlorobenzene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cell proliferation in the kidneys and livers of rats and mice exposed short-term to p-dichlorobenzene (p-DCB) was evaluated by immunohistochemical measurement of bromodeoxyuridine (BrdU) incorporation into nuclei of DNA-synthesizing cells. p-DCB was given by gavage at two doses up to 600 mg/kg body weight for 4 days. The cumulative fraction of proliferating cells was increased in the proximal tubule epithelial cells of male rats at the high dose, but not at the low dose nor in females at either dose using gamma-glutamyl transferase reaction to identify tubular cells. Also, no increase in cell proliferation was found in mouse kidneys. The fractions of proliferating cells in the livers of rats and mice of both sexes were also increased. The increased cell proliferation in only male rat kidney and in the livers of mice of both sexes correlates with the reported carcinogenic effects of p-DCB in those tissues. However, the finding that p-DCB also induced cell proliferation in the livers of rats of both sexes, which were not a site of p-DCB-induced tumors in bioassays, and in female mice at the low dose, which was not affected by an increase in tumors, reveals a lack of concordance and indicates that acute induction of cell proliferation is not sufficient to lead to carcinogenesis.
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  • 196
    ISSN: 1432-0738
    Keywords: Neurotransmitter ; Haloperidol ; Rat ; Brain -HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated the influence of the dopamine antagonist haloperidol on the neurotransmitter content in the developing rat brain. Dopamine (DA), serotonin (5-HT) and the corresponding metabolites dopac, HVA and HIAA were determined in the corpus striatum of the rat between day 1 and day 21 pn by HPLC with electrochemical detection. A consistent increase in the content of dopamine was found during postnatal development. The concentrations (ng/g wet tissue; mean ±standard deviation) increased from 793±237 on day 1 pn to 4584±581 on day 21 pn, but remained still lower than in adult animals (9763±494). Similar results were found for the metabolites dopac and HVA. The content of dopac increased from 59±22 (day 1 pn) to 551±59 (day 21 pn) and the content of HVA from 53±18 (day 1 pn) to 419±41 (day 21 pn). Both metabolites were also about two times lower than in adult animals (dopac 1090± 282, HVA 744± 206). In contrast to dopamine and its metabolites we found no age-dependent changes in the content of 5-HT from day 1 pn (99± 11) to day 14 pn(121±21). A remarkable increase in the content of 5-HT was seen from day 14 pn to day 21 pn (438±56), reaching almost adult levels (570±92). The metabolite HIAA was nearly three times higher on day 21 pn (610±123) than on day 14 pn (223±28) and two times higher than in adults (321±58). One hour after application of haloperidol to the pups (1 mg/kg body wt i.p.) a significant increase (i.e. day 21 pn) of dopac (1755±496) and HVA (966±279), but not of 5-HT (382±72) or HIAA (614±130) was detected.
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  • 197
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    Journal of cancer research and clinical oncology 119 (1992), S. 111-116 
    ISSN: 1432-1335
    Keywords: Aging ; Intrasplenic ovarian grafts ; Ovarian tumours ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Female rats at the age of 1, 3, and 14–16 months (“young”, “adult” and “old” groups respectively) were bilaterally ovariectomized and one of the removed ovaries was autoimplanted into the spleen. The total intrasplenic ovarian tumour incidence was equal in the rats subjected to the operation at 3 and 14–16 months (77.4% and 80.6% respectively) and tumours developed more frequently in rats exposed to surgery at the age of 1 month (94.5%),P〈0.05. The incidence of Sertoli and Leydig cell tumours was increased and their latency was decreased in the old group in comparison to the adult one. In rats exposed to the operation at the age of 3 months, granulosotheca cell tumours developed more frequently than other tumour types, and in the young group thecomas were discovered more often than in both older groups. Dysgerminomas and luteomas were discovered only in intrasplenic grafts of rats of the young group. It is supposed that the differences in structure and proliferative activity of various ovarian tissues between young, adult and old rats at the moment of intrasplenic transplantation, as well as the differences in their response to gonadotropic stimulation play a significant role in the development of ovarian tumours of varied histogenesis in the intrasplenic ovarian grafts.
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  • 198
    Electronic Resource
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    Psychopharmacology 107 (1992), S. 575-580 
    ISSN: 1432-2072
    Keywords: Novelty hypoalgesia ; Noradrenaline ; Naloxone ; Alpha-2 receptor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous research has shown that repeated daily pretreatment with the opiate receptor blocker naloxone retards the development of habituation to novelty-induced hypoalgesia. The present experiments were conducted in order to determine whether noradrenergic substrates mediate this effect. Animals in the NAL condition were administered 10 mg/kg naloxone prior to assessment of pain sensitivity on a 48.5° C hot plate. Control animals (SAL condition) were administered saline prior to pain assessment, and naloxone 2–4 h later. Paw lick latencies declined over repeated tests in SAL animals, suggesting the habituation of novelty hypoalgesia. Naloxone pretreatment attenuated this decline. The longer paw lick latencies observed in NAL condition animals were reduced by administration of 2 µg/kg clonidine, a specific noradrenergic alpha-2 receptor agonist, and enhanced in a dose dependent (0.5–4.0 mg/kg) fashion by the alpha-2 antagonist yohimbine. Clonidine and yohimbine either failed to alter pain reactivity in control animals, or produced less marked effects than those observed in naloxone-exposed animals. These results suggest that noradrenergic substrates mediate naloxone's effects on novelty hypoalgesia.
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  • 199
    ISSN: 1432-2072
    Keywords: MK-801 induced hypermotility ; Repeated treatment ; SCH 23390 ; YM 09151 ; 2 ; LY 171555-induced hyperactivity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The D2 or D1 dopamine receptor blockers (−)-sulpiride or SCH 23390 antagonized, in a dose dependent manner, the hypermotility induced by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.25 mg/kg IP). MK-801 induced hyperactivity was not detected when rats were observed on days 7, 14 or 21 of 21 daily injections of MK-801. This lack of hyperactivity was also noted 5 days after the last administration of the repeated treatment with MK-801. The hypermotility induced by the D2 dopamine receptor agonist LY 171555 (0.3 mg/kg IP) was reduced 5 days following repeated treatment (21 days) with MK-801, while no change in the behavioral responses to the selective D1 agonist, SKF 38393, or the mixed D1/D2 agent apomorphine was detected. The results, although suggesting the involvement of dopaminergic pathways in the behavioral effect of MK-801, are conflicting with regard to the underlying mechanisms and to the adaptive changes of dopaminergic system following repeated NMDA receptor blockade.
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  • 200
    ISSN: 1432-2072
    Keywords: Microdialysis ; 5-HT ; Ventral hippocampus ; Elevated X-maze ; Diazepam ; Ipsapirone ; F2692 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract One of the proposed mechanisms of action for the anxiolytic effects of the benzodiazepines is via a decrease in central serotonergic neurotransmission. The aim of this study was to combine in vivo microdialysis in the rat with behaviour on the elevated X-maze to determine changes in 5-HT release in the ventral hippocampus with concomitant measurement of behaviour. Twenty minutes exposure to the elevated X-maze resulted in an increase in extracellular 5-HT in the ventral hippocampus with no change in extracellular 5-HIAA. Restricting the rat to either the open or the closed arms produced an increase in extracellular 5-HT, however the increase in 5-HT when restricted to the open arms was not significantly greater than that on the closed arms. Forty minutes pretreatment with diazepam (2.5 mg kg−1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over 5 min and 20 min exposures of the rats to the X-maze. Diazepam had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the 5-HT1A receptor partial agonist ipsapirone (1 mg kg−1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus but did not produce behaviour different from vehicle controls after 5 or 20 min periods on the X-maze. Ipsapirone had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the novel anxiolytic F2692 (10 mg kg−1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over the 5 min but not the 20 min period when the rat was on the X-maze. F2692 reduced basal extracellular 5-HT levels both 20 min before exposure to the X-maze and when the animal was returned to the holding cage. The results are discussed based on the effects of these compounds on basal and elevated extracellular 5-HT levels and their behavioural profile on the X-maze.
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