NEUROLEPTIC DRUGS: A COMPARISON OF THEIR EFFECTS IN VIVO AND IN VITRO ON BRAIN DOPAMINERGIC SYSTEMS.
Item
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Title
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NEUROLEPTIC DRUGS: A COMPARISON OF THEIR EFFECTS IN VIVO AND IN VITRO ON BRAIN DOPAMINERGIC SYSTEMS.
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Identifier
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AAI8203299
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identifier
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8203299
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Creator
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LIN, CHUN WEL.
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Contributor
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Sherwin Wilk
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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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Health Sciences, Pharmacology
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Abstract
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The objective of this research was to examine the relationship between the antidopamine effects in vivo of antipsychotic drugs with their antidopamine effects in vitro. Antipsychotic drugs are believed to exert their clinical effect by the blockade of dopamine (DA) receptors. Biochemically, this effect can be monitored by measuring the increase in the turnover of DA neurons produced by these drugs, by the competition for the binding sites labelled with (3H)-neuroleptic drugs, or by the reversal of stimulation of adenylate cyclase by DA. The relative clinical potencies of neuroleptic drugs in general parallels their potencies in increasing DA turnover and in competing for binding sites labelled by (3H)-neuroleptics. Antagonism of adenylate cyclase stimulation correlates poorly with clinical potency. There are a number of antipsychotic drugs whose properties differ from typical neuroleptics. The benzamide neuroleptics metoclopramide and sulpiride, for example, increase DA turnover in vivo, but are weak in competing for (3H)spiroperidol(Spiro) sites and are ineffective in reversing the stimulation of adenylate cyclase. The anomalous properties of these benzamide drugs prompted us to (1) re-evaluate the validity of using the radioreceptor binding technique to predict antidopamine properties in vivo and (2) to develop a radioreceptor binding system which would help to elucidate the sites of action of the benzamide neuroleptics. In addition to binding studies in membrane fractions, we also studied binding to cryostat-cut slide mounted brain slices. In the first study, the effect of an extensive series of typical and atypical neuroleptic drugs on the binding of (3H)Spiro in calf striatal membrane fractions was assessed. Using 1 uM d-butaclamol to define the non-specific binding of (3H)Spiro and a rapid filtration technique, saturation of (3H)Spiro, kinetics of association and dissociation, and competition experiments were run. Results were analysed with the aid of the PROPHET computer, and methods of Hill, Scatchard, and Dixon were used to analyse the saturation and competition experiments. The potencies of antipsychotic drugs in this system were compared to their clinical potencies and their potencies in increasing the turnover of DA neurons in rat striatum and tuberculum olfactorium. Levels of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid were determined by gas chromatography. In the second study, (3H)dihydroergocryptine (DHE) was used as the radioligand. The specificity of binding was enhanced using a low concentration of the displacer, d-butaclamol. DHE was proposed to label a subpopulation of DA receptors which are independent of adenylate cyclase activity. Under these conditions, apparent DAergic sites have been defined which have high affinity for the benzamide neuroleptics as well as for a majority of typical neuroleptics. This study confirmed the antiDA properties of benzamide neuroleptics in vitro. In another study, binding of (3H)Spiro was assessed using a nM concentration of d-butaclamol as the displacer. The properties of this system was compared to the system using 1 uM d-butaclamol as the displacer. In the brain slice experiments, sites were labeled by (3H)Spiro and (3H)DHE and patterns of displacement of these sites by various typical and atypical neuroleptics were also examined.
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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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Biomedical Sciences
