Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats

Background: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, (effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF1 receptor antagonists on excessive ethanol self-administration in dependent rats. Methods. Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were. exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF, antagonists) and ethanol self-administration was measured. Results: The nonpeptide, small molecule CRF1 antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists bad no effect on ethanol self-administration in nondependent rats. Conclusions: These data demonstrate that CRF1 receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF1 antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.