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

Abstract

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 CRF(1) 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(1) antagonists) and ethanol self-administration was measured.

Results: The nonpeptide, small molecule CRF(1) 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 CRF(1) receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF(1) antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.

Figure 1

Chemical structures for antalarmin, MJL-1-109-2, and R121919.

Figure 2

Effects of antalarmin on ethanol and water self-administration in dependent and nondependent rats. Ethanol dependence was induced by intermittent exposure to ethanol vapors for 4 weeks and animals were subsequently tested for ethanol and water self-administration following 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals display a significant increase in ethanol lever pressing compared with nondependent animals. Antalarmin significantly decreases ethanol self-administration in withdrawn, dependent but not nondependent animals. Neither ethanol vapor exposure nor antalarmin alters water responding. *p < .001 compared with same drug dose in nondependent animals. #p < .01 compared with vehicle treatment in dependent animals.

Figure 3

Effects of MJL-1-109-2 on ethanol and water self-administration in dependent and nondependent rats. Ethanol dependence was induced by intermittent exposure to ethanol vapors for 4 weeks and animals were subsequently tested for ethanol and water self-administration following 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals display a significant increase in ethanol lever pressing compared with nondependent animals. MJL-1-109-2 significantly decreases ethanol self-administration in withdrawn, dependent but not nondependent animals. Neither ethanol vapor exposure nor MJL-1-109-2 alters water responding. *p < .0001 compared with same drug dose in nondependent animals. #p < .0001 compared with vehicle treatment in dependent animals.

Figure 4

Effects of R121919 on ethanol and water self-administration in dependent and nondependent rats. Ethanol dependence was induced by intermittent exposure to ethanol vapors for 4 weeks and animals were subsequently tested for ethanol and water self-administration following 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals display a significant increase in ethanol lever pressing compared with nondependent animals. R121919 significantly decreases ethanol self-administration in withdrawn, dependent but not nondependent animals. Neither ethanol vapor exposure nor R121919 alters water responding. *p < .001 compared with same drug dose in nondependent animals. #p < .0001 compared with vehicle treatment in dependent animals.