Effects of thioridazine and its metabolites on dopaminergic function: Drug metabolism as a determinant of the antidopaminergic actions of thioridazine

C. D. Kilts, D. L. Knight, Richard Mailman, E. Widerlöv, G. R. Breese

Research output: Contribution to journalArticle

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Abstract

The antidopaminergic properties of thioridazine (THD) and its major metabolites were evaluated using in vitro and in vivo estimates of dopaminergic function. THD-2-sulfone was more potent than, and THD-2-sulfoxide equipotent to, THD in displacing [3]spiperone from rat striatal membranes and in inhibiting dopamine-stimulated cyclic adenosine 3',5'-monophosphate synthesis in rat striatal homogenates. Other major THD metabolites were relatively inactive. These in vitro data suggest that THD, THD-2-sulfone and THD-2-sulfoxide are potent dopamine receptor blocking agents. Intraperitoneally administered THD antagonized amphetamine-induced locomotion and also increased the concentration of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in terminals of the nigrostriatal dopamine system. Conversely, THD administered i.c.v. into conscious animals, did not antagonize amphetamine-induced locomotion nor increase brain regional concentrations of DOPAC or HVA. On the other hand, the i.c.v. administration of THD-2-sulfone and THD-2-sulfoxide dose-dependently inhibited amphetamine-induced locomotion and also increased the concentrations of HVA and/or DOPAC in the striatum and olfactory tubercles. These apparently discrepant in vitro and in vivo data suggest that the biotransformation of THD is a major determinant in those actions of THD attributed to a blockade of dopamine receptors in the central nervous system.

Original languageEnglish (US)
Pages (from-to)334-342
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume231
Issue number2
StatePublished - Dec 1 1984

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Thioridazine
Dopamine Agents
Homovanillic Acid
Amphetamine
Locomotion
Corpus Striatum
Dopamine
Dopamine Receptors
Spiperone
3,4-Dihydroxyphenylacetic Acid
Acids
Biotransformation
Cyclic AMP
Central Nervous System
Membranes
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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abstract = "The antidopaminergic properties of thioridazine (THD) and its major metabolites were evaluated using in vitro and in vivo estimates of dopaminergic function. THD-2-sulfone was more potent than, and THD-2-sulfoxide equipotent to, THD in displacing [3]spiperone from rat striatal membranes and in inhibiting dopamine-stimulated cyclic adenosine 3',5'-monophosphate synthesis in rat striatal homogenates. Other major THD metabolites were relatively inactive. These in vitro data suggest that THD, THD-2-sulfone and THD-2-sulfoxide are potent dopamine receptor blocking agents. Intraperitoneally administered THD antagonized amphetamine-induced locomotion and also increased the concentration of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in terminals of the nigrostriatal dopamine system. Conversely, THD administered i.c.v. into conscious animals, did not antagonize amphetamine-induced locomotion nor increase brain regional concentrations of DOPAC or HVA. On the other hand, the i.c.v. administration of THD-2-sulfone and THD-2-sulfoxide dose-dependently inhibited amphetamine-induced locomotion and also increased the concentrations of HVA and/or DOPAC in the striatum and olfactory tubercles. These apparently discrepant in vitro and in vivo data suggest that the biotransformation of THD is a major determinant in those actions of THD attributed to a blockade of dopamine receptors in the central nervous system.",
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Effects of thioridazine and its metabolites on dopaminergic function : Drug metabolism as a determinant of the antidopaminergic actions of thioridazine. / Kilts, C. D.; Knight, D. L.; Mailman, Richard; Widerlöv, E.; Breese, G. R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 231, No. 2, 01.12.1984, p. 334-342.

Research output: Contribution to journalArticle

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T1 - Effects of thioridazine and its metabolites on dopaminergic function

T2 - Drug metabolism as a determinant of the antidopaminergic actions of thioridazine

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