Pimozide

Delayed onset of action at rat striatal pre- and postsynaptic dopamine receptors

B. A. McMillen, D. C. German, M. K. Sanghere, W. Warnack, P. A. Shore

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

It has been reported that the antipsychotic drug, pimozide, is unique in that it blocks postsynaptic dopamine (DA) receptors, but not presynaptic DA receptors. This was examined by comparing pimozide with haloperidol for time of onset of action in several experimental paradigms designed to demonstrate blockade of pre- and postsynaptic striatal DA receptors. Haloperidol (1.0 mg/kg s.c.) caused near maximum catalepsy scores within 90 min after injection, a time when twice as much pimozide had yet to produce catalepsy. Pimozide consistently exhibited a delayed onset of action on several dopaminergic biochemical parameters including: increased striatal DA metabolism, increased DA synthesis and inhibition of apomorphine action at presynaptic DA receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apormorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay of pimozide action occurs at both postsynaptic and presynaptic DA receptors. It is known that pimozide binds with high affinity to neuroleptic binding sites (in vitro) and rapidly enters the brain after systemic injection. Pretreatment of animals with SKF 525-A, an inhibitor of liver mixed-function oxidase enzymes, had little or no effect on pimozide's actions, suggesting that formation of an active metabolite is not the cause of pimozide's delayed actions. The reason for the delayed action is unclear, but pimozide will interact with both pre- and postsynaptic DA receptors if given sufficient time.

Original languageEnglish (US)
Pages (from-to)150-155
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume215
Issue number1
StatePublished - 1980

Fingerprint

Pimozide
Corpus Striatum
Dopamine Receptors
Presynaptic Receptors
Catalepsy
Dopamine
Apomorphine
Haloperidol
Antipsychotic Agents
Proadifen
Injections
Mixed Function Oxygenases
Binding Sites

ASJC Scopus subject areas

  • Pharmacology

Cite this

Pimozide : Delayed onset of action at rat striatal pre- and postsynaptic dopamine receptors. / McMillen, B. A.; German, D. C.; Sanghere, M. K.; Warnack, W.; Shore, P. A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 215, No. 1, 1980, p. 150-155.

Research output: Contribution to journalArticle

@article{8e2a21ddd90c4e2d92c746531b511202,
title = "Pimozide: Delayed onset of action at rat striatal pre- and postsynaptic dopamine receptors",
abstract = "It has been reported that the antipsychotic drug, pimozide, is unique in that it blocks postsynaptic dopamine (DA) receptors, but not presynaptic DA receptors. This was examined by comparing pimozide with haloperidol for time of onset of action in several experimental paradigms designed to demonstrate blockade of pre- and postsynaptic striatal DA receptors. Haloperidol (1.0 mg/kg s.c.) caused near maximum catalepsy scores within 90 min after injection, a time when twice as much pimozide had yet to produce catalepsy. Pimozide consistently exhibited a delayed onset of action on several dopaminergic biochemical parameters including: increased striatal DA metabolism, increased DA synthesis and inhibition of apomorphine action at presynaptic DA receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apormorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay of pimozide action occurs at both postsynaptic and presynaptic DA receptors. It is known that pimozide binds with high affinity to neuroleptic binding sites (in vitro) and rapidly enters the brain after systemic injection. Pretreatment of animals with SKF 525-A, an inhibitor of liver mixed-function oxidase enzymes, had little or no effect on pimozide's actions, suggesting that formation of an active metabolite is not the cause of pimozide's delayed actions. The reason for the delayed action is unclear, but pimozide will interact with both pre- and postsynaptic DA receptors if given sufficient time.",
author = "McMillen, {B. A.} and German, {D. C.} and Sanghere, {M. K.} and W. Warnack and Shore, {P. A.}",
year = "1980",
language = "English (US)",
volume = "215",
pages = "150--155",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Pimozide

T2 - Delayed onset of action at rat striatal pre- and postsynaptic dopamine receptors

AU - McMillen, B. A.

AU - German, D. C.

AU - Sanghere, M. K.

AU - Warnack, W.

AU - Shore, P. A.

PY - 1980

Y1 - 1980

N2 - It has been reported that the antipsychotic drug, pimozide, is unique in that it blocks postsynaptic dopamine (DA) receptors, but not presynaptic DA receptors. This was examined by comparing pimozide with haloperidol for time of onset of action in several experimental paradigms designed to demonstrate blockade of pre- and postsynaptic striatal DA receptors. Haloperidol (1.0 mg/kg s.c.) caused near maximum catalepsy scores within 90 min after injection, a time when twice as much pimozide had yet to produce catalepsy. Pimozide consistently exhibited a delayed onset of action on several dopaminergic biochemical parameters including: increased striatal DA metabolism, increased DA synthesis and inhibition of apomorphine action at presynaptic DA receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apormorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay of pimozide action occurs at both postsynaptic and presynaptic DA receptors. It is known that pimozide binds with high affinity to neuroleptic binding sites (in vitro) and rapidly enters the brain after systemic injection. Pretreatment of animals with SKF 525-A, an inhibitor of liver mixed-function oxidase enzymes, had little or no effect on pimozide's actions, suggesting that formation of an active metabolite is not the cause of pimozide's delayed actions. The reason for the delayed action is unclear, but pimozide will interact with both pre- and postsynaptic DA receptors if given sufficient time.

AB - It has been reported that the antipsychotic drug, pimozide, is unique in that it blocks postsynaptic dopamine (DA) receptors, but not presynaptic DA receptors. This was examined by comparing pimozide with haloperidol for time of onset of action in several experimental paradigms designed to demonstrate blockade of pre- and postsynaptic striatal DA receptors. Haloperidol (1.0 mg/kg s.c.) caused near maximum catalepsy scores within 90 min after injection, a time when twice as much pimozide had yet to produce catalepsy. Pimozide consistently exhibited a delayed onset of action on several dopaminergic biochemical parameters including: increased striatal DA metabolism, increased DA synthesis and inhibition of apomorphine action at presynaptic DA receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apormorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay of pimozide action occurs at both postsynaptic and presynaptic DA receptors. It is known that pimozide binds with high affinity to neuroleptic binding sites (in vitro) and rapidly enters the brain after systemic injection. Pretreatment of animals with SKF 525-A, an inhibitor of liver mixed-function oxidase enzymes, had little or no effect on pimozide's actions, suggesting that formation of an active metabolite is not the cause of pimozide's delayed actions. The reason for the delayed action is unclear, but pimozide will interact with both pre- and postsynaptic DA receptors if given sufficient time.

UR - http://www.scopus.com/inward/record.url?scp=0019296405&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019296405&partnerID=8YFLogxK

M3 - Article

VL - 215

SP - 150

EP - 155

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -