Coadministration of haloperidol and SCH-23390 prevents the increase in "perforated" synapses due to either drug alone

Perforated synapses, which have a discontinuous density along the postsynaptic membrane, undergo changes in numbers under various experimental conditions. We have previously shown that 14-day administration of haloperidol, a typical neuroleptic which induces extrapyramidal side effects (EPS) and tardive dyskinesia (TD) in patients, causes an increase in the percentage of perforated synapses within the caudate nucleus. This increase was reversed if the animals were taken off the drug for an equal period of time (14 days). There was no effect within the nucleus accumbens. The atypical antipsychotic drug, clozapine, which when administered precipitates a very much lower incidence of EPS and TD, had no effect on the percentage of perforated synapses within either the caudate or nucleus accumbens. Because clozapine binds to both dopamine (DA) D₁ and D₂ receptors, it was of interest to determine if any changes in perforated synapses occurred following administration of the specific D₁ antagonist, SCH-23390. Furthermore, because the action of D₂ agonists may be dependent on the activation of the D₁ receptor, we asked whether concomitant blockade of the D₁ receptor could prevent the increase in perforated synapses due to the action of haloperidol, a drug which upregulates D₂ receptors. We found that 14-day treatment with SCH-23390 (1.0 mg/kg per day) or haloperidol (0.5 mg/kg per day) caused an increase in the percentage of perforated synapses within the caudate but not the nucleus accumbens. There was a corresponding increase in DA D₁ and D₂ receptors in the caudate following administration of SCH-23390 or haloperidol, respectively. Coadministration of the two drugs prevented the increase in perforated synapses within the caudate, even though D₁ and D₂ receptors were significantly increased. Our data suggest that the regulation of perforated synapses and DA receptors are independent events. This could be explained anatomically if the two DA receptor subtypes are located on different striatal neurons whose efferent projections are initially distinct but converge in a common brain area. Administration of SCH-23390 might, therefore, attenuate the EPS and TD associated with haloperidol treatment.