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
C2 - 6109013
AN - SCOPUS:0019296405
SN - 0022-3565
VL - 215
SP - 150
EP - 155
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -