NEUROPHARMACOLOGY AND METABOLISM OF PHENOTHIAZINES

Project: Research project

Description

This proposal will investigate the relationship between metabolism and
neuropharmacology of three structurally dissimilar phenothiazine
antipsychotic drugs [thioridazine (Mellaril), trifluoperazine (Stelazine),
and chlorpromazine (Thorazine)]. The primary goal of the
neuropharmacological experiments is to compare the antidopaminergic
activity of the parent phenothiazines with their major metabolites. The in
vitro techniques to be used include various radioligand binding assays
(e.g., with [3H]-spiperone and [3H]-dopamine), and the ability of drugs to
affect dopamine-stimulated adenylate cyclase activity. Another in vitro
measure to bridge the gap between data from the intact animal vs. that from
brain homogenates, are effects of these drugs on pre- and post-synaptic
receptors modulating the release of dopamine and acetylcholine from slices
of striatum or other regions. In vitro effects on other neurotransmitter
systems (e.g., [3H]-QNB or [3H]-WB-4101 binding) will also be examined. In
vivo studies will determine the ability of the drug metabolites or their
parent compounds to inhibit amphetamine- or apomorphine-induced behaviors
(e.g., stereotyped behavior, aggression, and locomotion) and to alter
biochemical estimates of the activity of dopamine neurons using
neurochemical methods to evaluated DOPAC, HVA, 1-DOPA, etc., as required.
Both intracerebroventricular and peripheral routes of drug administration
will be used in the in vivo experiments. Finally, the effects of
withdrawal from chronic drug administration will be measured to determine
if behavioral and neurochemical changes observed are a function of the
metabolites formed from the parent compound. These functional and
biochemical data relevant to these phenothiazines and their metabolites
will be compared to similar studies with a classical non-phenothiazine
neuroleptic (haloperidol) and a compound, SCH 23390, purported to be a
specific D1 dopamine antagonist. Mechanisms of metabolism will be
determined, focusing on two distinct enzyme systems, the flavin-containing
monooxygenase (EC1.14.13.8) and cytochrome P450 monooxygenases. The
relative role of the P450 and FCM enzymes in the bioformation of
pharmacologically active metabolites, and the effects of chronic
administration of these drugs on enzyme activity, will be determined.
Species differences in enzyme activity will be exploited by using a species
(e.g., hamsters) that should produce patterns of metabolites in blood that
are similar to humans and unlike rats.
StatusFinished
Effective start/end date12/1/841/31/91

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Neuropharmacology
Phenothiazines
Pharmaceutical Preparations
Thioridazine
Trifluoperazine
Aptitude
Chlorpromazine
Cytochrome P-450 Enzyme System
Dopamine
Enzymes
Stereotyped Behavior
Spiperone
3,4-Dihydroxyphenylacetic Acid
Radioligand Assay
Dopamine Agents
Dopamine Antagonists
Apomorphine
Dopaminergic Neurons
Haloperidol
Amphetamine