HALOPERIDOL TREATMENT DIFFERENTIALLY REGULATES [H-3] DTG AND [H-3] (-3-PPP LABELED SIGMA-BINDING SITES())

The effect of repeated haloperidol administration on sigma binding sit es in brain membranes was assessed using H-3](+)-3-(3-hydroxyphenyl)-N -(1-propyl)piperidine ((+)-3-PPP) and [H-3]1,3-di-o-tolylguanidine (DT G). Administration of haloperidol (1 mg/kg, i.p.) to guinea pigs for 1 4 consecutive days followed by a 4 day drug-free period prior to sacri fice resulted in 75% and 6% decreases in the specific binding of H-3]( +)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [H-3]1,3-di-o-tolylg uanidine, respectively, when measured using a single concentration (2 nM) of radioligand. Scatchard analysis revealed a reduction in both th e maximum number of H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites and the affinity of these sites for the radioligand; th e potency of 1,3-di-o-tolylguanidine to inhibit H-3](+)-3-(3-hydroxyph enyl)-N-(1-propyl)piperidine binding was also reduced. In parallel stu dies, the potency of 1,3-di-o-tolylguanidine to inhibit [H-3]1,3-di-o- tolylguanidine binding was unaffected by haloperidol treatment, but th e potency of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine against [H -3]1,3-di-o-tolylguanidine was reduced 3-fold. Phenytoin, which increa sed (10-fold) the potency of dextromethorphan to inhibit [H-3]1,3-di-o -tolylguanidine binding in control membranes, had no effect in membran es obtained from haloperidol-treated animals. The reduction in H-3](+) -3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was dependent upon the duration of the drug-free period and amounted to 73% and 25% in b rain membranes prepared from animals sacrificed 14 days and 28 days, r espectively, following cessation of drug treatment. Repeated administr ation of other antipsychotic and sigma agents including DTG, dextromet horphan, spiperone, chlorpromazine and clozapine had no effect on H-3] (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine or [H-3]1,3-di-o-tolylg uanidine binding. These findings suggest that repeated haloperidol adm inistration selectively regulates H-3](+)-3-(3-hydroxyphenyl)-N-(1-pro pyl)piperidine binding in guinea pig brain membranes. However, the obs ervations that repeated drug treatment resulted in (1) reduced affinit y of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine for [H-3]1,3-di-o- tolylguanidine binding sites, and (2) a loss of the ability of phenyto in to increase dextromethorphan's potency against [H-3]1,3-di-o-tolylg uanidine, suggest that H-3](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperid ine and [H-3]1,3-di-o-tolylguanidine binding sites are distinct but fu nctionally coupled.