Abstract The effects of cortical spreading depression (SD) on evoked dopamine release in mesolimbic (nucleus accumbens) and nigrostriatal (nucleus caudatus) terminal fields were studied by in vivo voltammetry in anesthetized rats. Dopamine release was evoked by electrical stimulation of medial forebrain bundle (20 Hz, 100 pulses). Local application of 3 M KCl on the dura initiated SD in the cortex. It was found that SD modulated evoked dopamine release in subcortical structures at the same time when the wave of depression of cortical activity reached reciprocally connected subcortical areas. This cortical depression increased stimulated dopamine release in the nucleus accumbens and decreased dopamine release in the nucleus caudatus. In agreement with these results, electrical stimulation of the prefrontal cortex at 20 Hz, synchronized with medial forebrain bundle stimulation, decreased evoked dopamine release in the nucleus accumbens. Areas of the cortex which modulated dopamine release in these two terminal fields were spatially separated by at least 5 mm from each other. It is proposed that depression and activation of evoked dopamine release in the nucleus caudatus and nucleus accumbens following SD are indicative of tonic activation of the nigrostriatal and tonic inhibition of the mesolimbic dopaminergic terminals by cortex in normal conditions. SD in the cortex, modulating neurotransmitter release in subcortical structures, may have a general impact on redistribution of oxygen supply in these subcortical areas and on behavior associated with brain trauma, migraine, insult or seizures, i.e. the kind of neuropathology which may cause SD type phenomena also in human brain.