Neuropharmacologic characterization of strychnine seizure potentiation in the inferior olive lesioned rat.
Item
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Title
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Neuropharmacologic characterization of strychnine seizure potentiation in the inferior olive lesioned rat.
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Identifier
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AAI8914738
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identifier
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8914738
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Creator
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Anderson, Melissa Currie.
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Contributor
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Adviser: Melvin H. Van Woert
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience | Psychology, Psychobiology
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Abstract
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Cerebellar stimulation is associated with anticonvulsant activity in several animal models. There are two afferent inputs to cerebellar Purkinje cells: (1) parallel fibers, which relay mossy fiber input, from brainstem, spinal cord, cerebral cortex and cerebellum, and (2) climbing fibers, arising from the inferior olive. Both climbing and parallel fibers release excitatory amino acid neurotransmitters (glutamate and/or aspartate), which stimulate Purkinje cells and cause GABA release in the deep cerebellar nuclei. Climbing fibers also exert tonic inhibition over Purkinje cell activity by producing an absolute refractory period following stimulation, rendering Purkinje cells unresponsive to parallel fibers.;Climbing fiber deafferentation by bilateral inferior olive lesions produced a specific decrease in threshold for strychnine-seizures in the rat. Inferior olive lesions produced no change in threshold to seizures induced by picrotoxin, bicuculline or pentylenetetrazole. Inferior olive lesions also produced abnormal motor behavior including, myoclonus, backward locomotion and hyperextension, which was significantly aggravated by strychnine, brucine, picrotoxin, bicuculline and pentylenetetrazole.;Inferior olive lesions produced a significant increase in quisqualate sensitive {dollar}\rm\lbrack\sp3H\rbrack AMPA{dollar} ((RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) binding to cerebellar membranes. AMPA is a glutamate analog with high affinity for quisqualate sensitive receptors.;Systemic administration of glutamate diethylester, a quisqualate selective glutamate antagonist, caused reversal of inferior olive lesion induced decrease in strychnine-seizure threshold. This suggests that the behavioral effect of inferior olive lesions (i.e., decreased threshold for strychnine-seizure) is medicated by an increase in quisqualate sensitive glutamate receptors in cerebellum. Increased receptor binding may be the result of ectopic spine formation on Purkinje cells due to heterotypic reinnervation by parallel fibers.;A similar proconvulsive phenomenon occurs following systemic administration of azaspirodecanedione anxiolytics; buspirone, gepirone and isapirone. Strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive. This observation indicates that buspirone-induced decrease in strychnine-seizure threshold does not require intact inferior olive-climbing fiber pathways. Although the azaspirodecanediones have high affinity for 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} sites, the selective 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} agonist, 8-OH DPAT, had no effect on strychnine seizure threshold.;Decreased threshold for strychnine-seizure produced by bilateral inferior olive lesion and azaspirodecanedione pretreatment may be mediated through increased Purkinje cell activity and resultant decreased cerebellar efferent output.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
