The effects of acute administration of phencyclidine, an indirect dopamine agonist, on biochemical indices of dopaminergic activation were examined in mesocortical, mesolimbic and nigrostriatal regions of the rat. High doses (10 mg/kg) of phencyclidine resulted in a marked increase in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in all mesolimbic and mesocortical sites examined, as well as in the ventral tegmental area, source of the dopaminergic innervation of mesolimbic/cortical sites. In contrast, levels of both metabolites decreased in the striatum and tended to decrease in the substantia nigra, source of the striatal dopaminergic innervation. The metabolite response to phencyclidine was dose-related. These data indicate that the mesolimbic and mesocortical dopaminergic neurons are activated by phencyclidine. Since the firing rate of both A10 (ventral tegmental area) and A9 (substantia nigra) dopamine neurons has previously been shown to be increased by phencyclidine, these data suggest that phencyclidine results in a differential regulation of presynaptic release of dopamine in mesolimbic/cortical as opposed to nigrostriatal dopaminergic regions.