Effects of CP 154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats

We examined the influence of CP 154,526, a selective antagonist of corticotropin-releasing factor (CRF)1 receptors, in the locomotor, sensitizing, discriminative stimulus and rewarding effects of cocaine, as well as on the cocaine-induced reinstatement of cocaine-seeking behavior in male Wistar rats. CP 154,526 in doses of 5, 10 and 20 mg/kg, which did not affect basal locomotor activity, dose-dependently reduced the hyperactivation evoked by cocaine. To assess the effects of CP 154,526 on the expression of cocaine sensitization, the rats were injected with either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) after pretreatment with saline or CP 154,526 on day 5 of withdrawal. The cocaine-induced hyperactivity in sensitized rats was reduced by CP 154,526 (10 and 20 mg/kg). In rats trained to discriminate cocaine (10 mg/kg) from saline, pretreatment with CP 154,526 (5-20 mg/kg) did not affect the cocaine (1.25-10 mg/kg)-induced discriminative stimulus effects. In a self-administration model, the rats were trained to self-administer cocaine (0.5 mg/kg/infusion) in the FR 5 schedule of reinforcement. Administration of CP 154,526 (10-20 mg/kg) did not alter the rewarding effects of cocaine, assessed as the number of active-lever presses and infusions; however, following a 10-day extinction phase, CP 154,526 (5-20 mg/kg) significantly decreased in a dose-dependent manner the cocaine (10 mg/kg) priming-induced reinstatement of cocaine-seeking behavior. The present study implies that CRF1 receptors control the expression of cocaine hyperactivation and sensitization as well as the cocaine-induced relapse behavior, but do not play any role in cocaine discrimination and self-administration. These findings may suggest that CRF1 receptor antagonists should be considered as possible medications in the treatment of cocaine addiction.