THYROTROPIN-RELEASING HORMONE (TRH) ANTAGONISM OF PENTOBARBITAL NARCOSIS: CENTRAL NEUROMODULATION.
Item
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Title
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THYROTROPIN-RELEASING HORMONE (TRH) ANTAGONISM OF PENTOBARBITAL NARCOSIS: CENTRAL NEUROMODULATION.
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Identifier
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AAI8119656
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identifier
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8119656
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Creator
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HIRSCH, MICHAEL DAVID.
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Contributor
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Prof. Walter B. Essman
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Date
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1981
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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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Psychology, Physiological
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Abstract
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A series of eight experiments were undertaken to characterize the possible central neuromodulatory mechanisms underlying thyrotropin releasing hormone (TRH) antagonism of barbiturate-induced narcosis in the CF-1(,S) mouse brain on five levels: (a)physico-chemical, (b)neurochemical, (c)physiological, (d)psychopharmacological, and (e)behavioral. These experiments consisted of studies utilizing behavioral pharmacology, biochemical assays, in vitro competitive displacement {lcub}('3)H{rcub}-TRH radioreceptor assays, and in vivo radiochemical assays. The present results support the findings of other workers that TRH is efficacious both in vivo and in vitro in the antagonism of central barbiturate actions. Dose-response effects were found in this paradigm for two month old mice but not in three month olds.;This significant age-related difference in the TRH effect appears to be related to ontogenetic differences in hepatic drug metabolism since the biochemical results indicated that there are significant age-related differences in mouse brain concentrations of pentobarbital following intraperitoneal administrations of the drug. It can be assumed that TRH does not appear to alter hepatic metabolism of barbiturates in these experiments since brain levels of the administered drug are unaltered by central peptide vs. physiological saline injections. The central administrations were effected by a new intraventricular (i.vt.) technique developed for this procedure.;The interinjection duration (IID) between TRH and pentobarbital administrations appears to be an important variable influencing behavioral outcomes in the analeptic paradigm: Delivery of drug combinations in close temporal proximity induces optimal analeptic and nonspecific effects. Several proposed models--age-related, toxic-lethal, locomotor activity, spare receptor, and cooperativity phenomena--have been advanced to explain the interaction of these two effects.;The results also indicate no cyclical diurnal variations in TRH's analeptic actions, an expected result since central peptide activity has been previously found to be independent of pituitary functions.;The radioreceptor and radiochemical results also support the findings of other investigators as well as the present behavioral pharmacology findings: Three barbiturate analogues--phenobarbital, pentobarbital, the thiopental--appear to be effective competitive inhibitors of {lcub}('3)H{rcub}-TRH in the radioreceptor assay. This assay also indicates that there are significant regional differences in the degree of barbiturate inhibition at presynaptic vs. postsynaptic specific high-affinity TRH binding sites. The radiochemical data closely matches the radioreceptor data and indicate that presynaptic and postsynaptic TRH receptors of the limbic forebrain region are strongly implicated in the TRH analeptic mechanism.
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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.
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Program
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Neuropsychology
