Corticotropin-Releasing Factor 1 Antagonists Selectively Reduce Ethanol Self-Administration in Ethanol-Dependent Rats

• Published in: Biological psychiatry (1969) 2007-01, Vol.61 (1), p.78-86
• Main Authors: Funk, Cindy K, Zorrilla, Eric P, Lee, Mei-Jing, Rice, Kenner C, Koob, George F
• Format: Article
• Language: English
• Subjects: Alcohol; Alcoholism - drug therapy; Alcoholism - psychology; Animals; Behavior, Animal - drug effects; Central Nervous System Depressants - administration & dosage; Conditioning, Operant - drug effects; corticotropin-releasing factor; Corticotropin-Releasing Hormone - antagonists & inhibitors; dependence; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol - administration & dosage; Hormone Antagonists - chemistry; Hormone Antagonists - therapeutic use; Male; Psychiatry; Pyrimidines - therapeutic use; Pyrroles - therapeutic use; rat; Rats; Rats, Wistar; Self Administration - methods; self-administration; Triazines - therapeutic use; withdrawal
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2006.03.063

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 (CRF1 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 had 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.