Both the behavioral sensitization syndrome and the changes in the responsiveness of striatal neurons evoked by chronic cocaine exposure may be linked to enhanced neocortical activity, yet a direct demonstration of the effects of cortical stimulation on these parameters is lacking. We have found that repeated stimulation of the rat prelimbic cortex with picrotoxin (0.25 microg/0.25 microl, five injections on alternate days followed by 7-day withdrawal) contributed to increase c-Fos protein expression in the striosomes of the dorsolateral striatum, while producing the opposite effect in the matrix compartment, after a single exposure to cocaine (25 mg/kg). Moreover, rats exposed to cortical stimulation showed decreased locomotor activation but enhanced stereotypy following acute cocaine treatment. Thus, pulsatile stimulation of the prelimbic cortex facilitated modifications in striatal activity typically produced by chronic cocaine treatment and sensitized drug-naive animals to acute cocaine challenge. These results suggest that enhanced activation of the prelimbic cortex may contribute to the long-term adaptations induced by cocaine on neural activity and behavior.