CP-154,526, A SELECTIVE, NONPEPTIDE ANTAGONIST OF THE CORTISOTROPIN-RELEASING FACTOR(1) RECEPTOR ATTENUATES STRESS-INDUCED RELAPSE TO DRUG SEEKING IN COCAINE-TRAINED AND HEROIN-TRAINED RATS

We have found that peptide antagonists of corticotropin-releasing fact or (CRF) receptors attenuate reinstatement of heroin and cocaine seeki ng induced by footshock. Here we examined the effect of a nonpeptide, selective CRF1 receptor antagonist. CP-154.526, on reinstatement of he roin and cocaine seeking induced by footshock. Rats were trained to se lf-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, IV, r espectively) for 9-12 days. Extinction sessions were given for up to I t days, during which saline was substituted for the drugs. Tests for r einstatement were then conducted after exposure to intermittent footsh ock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with C P-154,526 (15 and 30 mg/kg, SC) significantly attenuated the reinstate ment effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate expe riment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performanc e deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stress ors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use.