Corticotropin-releasing factor (CRF) has been suggested to play an important role in the development of drug dependence and withdrawal. Based on the recent finding that CRF receptor antagonists inhibit the stress-induced relapse to opiate dependence and attenuate anxiety-like responses related to cocaine withdrawal, the present experiment was performed to examine the possible effect of different CRF receptor antagonists on reactivation of cocaine-conditioned place preference induced by cocaine and stress in rats. The results show that a single injection of cocaine (10 mg/kg, i.p.) could reactivate cocaine-conditioned place preference following a 28-day extinction, and pretreatment with i.c.v. 10 μg α-helical CRF, a nonspecific CRF receptor antagonist, significantly attenuated this reactivation of conditioned place preference. However, pretreatment with i.p. 1 or 10 mg/kg CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamine), a specific CRF receptor subtype 1 antagonist, and i.c.v. 1 or 10 μg AS-30 ([d-Phe¹¹,His¹²]Svg-(11-40)), a specific CRF receptor subtype 2 antagonist, failed to show the same effects. In addition, a single footshock stress also elicited the reactivation of cocaine-conditioned place preference following a 28-day extinction and pretreatment with α-helical CRF (10 μg, i.c.v.) and CP-154,526 (1 or 10 mg/kg, i.p.) significantly blocked this effect. In contrast, pretreatment with AS-30 at a dose of 1 or 10 μg (i.c.v.) did not affect the stress-induced reactivation of cocaine-conditioned place preference. The present study demonstrated that CRF receptor type 1, but not CRF receptor type 2, mediates the stress-induced reactivation of cocaine-conditioned place preference. These findings suggest that CRF receptor subtype 1 antagonists might be of some value in the treatment and prevention of stress-induced relapse to drug dependence long after detoxification.