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 receptors. In electrophysiological studies, pimozide did not block the ability of apomorphine to inhibit DA impulse flow if given 5 to 10 min before apomorphine, but was effective if longer pretreatment times were allowed. These data indicate that a delay or 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 pimoxide'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.