CLOZAPINE DECREASES SEROTONIN EXTRACELLULAR LEVELS IN THE NUCLEUS-ACCUMBENS BY A DOPAMINE RECEPTOR-INDEPENDENT MECHANISM

By using brain microdialysis, clear differences in the effects of the systemic administration of clozapine and haloperidol on the extracellular concentration of dopamine (DA) and serotonin (5-HT) were found in the nucleus accumbens of freely moving rats. Haloperidol (0.5 mg/kg s.c.) significantly increased DA (ca. 40%) but did not modify 5-HT extracellular concentration, while clozapine (5 mg/kg s.c.) significantly decreased 5-HT (ca. 40%) but did not change DA concentration. Locally infused, clozapine (10(-5) M) significantly increased DA (75%) and reduced 5-HT extracellular concentration (50%). The reduction of 5-HT cannot be explained by a clozapine-induced blockade of DA receptors, because the local infusion (10(-5) M) of the DA D-2-like antagonist raclopride and the DA D-1-like antagonist SCH 23390 significantly increased DA (ca. 300% and 200%, respectively) but did not modify 5-HT extracellular concentration. Conversely, the DA D-2-like agonist quinpirole and the DA D-1-like agonist SKF-38393 significantly decreased (ca. 60% in both cases) DA extracellular concentration without affecting that of 5-HT. The present results indicate that clozapine displays a powerful anti-serotoninergic effect by inhibiting 5-HT release in the nucleus accumbens, an effect probably derived from the reduction of firing activity at the dorsal raphe and by local mechanisms that may involve some 5-HT receptor subtype(s).