Using intracranial microdialysis, the effect of repeated cocaine (30 mg/kg i.p.) versus saline administration for 10 consecutive days upon basal and stimulated release of corticotropin-releasing factor (CRF) was examined in the central amygdaloid nucleus (CeA) of anesthetized rats. No significant differences in basal CRF levels between daily cocaine and saline treated groups were found. However, after cocaine challenge (10 mg/kg i.p.) the increase in CRF overflow was significantly greater in cocaine- as opposed to saline-pretreated rats (266 +/- 55.4% versus 149 +/- 8.5% of basal levels). Local administration of 4-aminopyridine produced a significant increase in CRF efflux (195 +/- 58.5%) in daily cocaine-treated rats with only a weak response in the control group (127 +/- 30.9%). These data demonstrate that repeated administration of cocaine enhances cocaine-induced release of CRF in the rat CeA. The sensitization of CRF release may play a significant role in psychostimulant-induced sensitization phenomena.