Neostriatal and mesolimbic neurons: Dose-dependent effects of clozapine

To determine whether clozapine, an antipsychotic drug devoid of extrapyramidal side effects, acts preferentially on neurons in the nucleus accumbens rather than in the neostriatum, an analysis of clozapine-induced changes in spontaneous neuronal activity was performed on locally anesthetized, immobilized rats. In both brain sites, intraperitoneal administration of clozapine (10, 20 or 80 mg/kg) produced a comparable dose-dependent increase in neuronal activity. Haloperidol, at a dose (2.0mg/kg) that typically elicits extrapyramidal side effects in rats, also increased the firing rate of neurons in the neostriatum and nucleus accumbens. However, haloperidol produced a greater effect on neuronal activity in the neostriatum during the first 15 min after injection, whereas 80 mg/kg clozapine was more effective during this period in the nucleus accumbens. In contrast, the neuronal response to the lower doses of clozapine paralleled that produced by haloperidol in the neostriatum; no differential regional effects were recorded at any time after injection of 10 or 20 mg/kg clozapine. The results suggest that the lack of extrapyramidal side effects associated with clozapine cannot be simply explained by a selective action of this drug on neurons in the nucleus accumbens.