The Involvement of Sigma and Phencyclidine Receptors in the Action of Antipsychotic Drugs

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Abstract
An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d‐amphetamine and MK‐801), as well in the radioligand binding studies against3H‐spiperone (dopamine2‐receptors) and3H‐haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK‐801‐induced motor excitation in the mouse. A nearly 3‐fold lower dose of clozapine was needed to block the effect of MK‐801 (6.4 μmol/kg) as compared to the action of amphetamine (17 μmol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine‐induced aggressiveness in the rat. After long‐term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2‐receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK‐801 in rats. Simultaneously with a behavioural change the density of3H‐TCP binding sites in the rat forebrain was elevated after long‐term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.