Antipsychotic drugs are traditionally classified as typical or atypical on the basis of their property to cause or not to cause extrapyramidal side-effects. A widely accepted selectivity for the mesolimbic, vs. the nigrostriatal, dopaminergic system is postulated to underlie the existence of fewer or no extrapyramidal side-effects during treatment with atypical neuroleptics. In order to verify this hypothesis we examined the effect of acute clozapine on nigrostriatal dopaminergic neurons recorded from non-anaesthetised and from chloral hydrate-anaesthetised rats. Extracellular single-unit recording coupled with antidromic activation from the neostriatum was used. Intravenous administration of cumulative doses of clozapine (1.25-10 mg/kg) increased the firing rate of nigrostriatal dopaminergic neurons in non-anaesthetised rats, but failed to significantly modify the activity of the same units under chloral hydrate anesthesia. These results indicate that acute clozapine activates nigrostriatal dopamine cells in non-anaesthetised rats and cast doubts about a direct link between the lack of significant extrapyramidal side-effects and the selectivity of atypical neuroleptics, such as clozapine, for the mesolimbic dopamine system.