Elsevier

Biological Psychiatry

Volume 61, Issue 1, 1 January 2007, Pages 78-86
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2006.03.063Get rights and content

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.

Section snippets

Animals

Fifty-six adult male Wistar rats weighing 180 to 200 grams at the start of the experiment were obtained from Charles River Laboratory (Kingston, New York). Animals were housed two to three per cage with food and water available ad libitum. Lights were on a 12-hour light/dark cycle, lights on at 6:00 am. All procedures met the guidelines of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (National Research Council 1996).

Drugs

Ethanol (10% wt/vol) was prepared

Effects of the CRF1 Specific Antagonist Antalarmin on Ethanol and Water Self-Administration in Dependent and Nondependent Rats

For the antalarmin group (n = 9), animal weights at the end of the experiment were 591.9 ± 53.6 grams for nondependent rats and 580 ± 14.9 grams for dependent rats. The mean blood alcohol level across the entire period of ethanol vapor exposure was 189.8 ± 24.7 mg/dL. Figure 2 shows the effects of antalarmin (0, 10.0, 20.0 mg/kg, IP) on ethanol and water self-administration in dependent versus nondependent animals.

In the 30-minute test session, following vehicle injection (.5%

Discussion

Excessive, uncontrolled drinking and the presence of a withdrawal syndrome following cessation of alcohol intake are two of the diagnostic criteria for dependence in humans (American Psychiatric Association 1994). Further, human alcoholics will report that the negative affect state, especially enhanced anxiety and stress, experienced during withdrawal is the main factor eliciting relapse and binge drinking during periods of abstinence (Hershon 1977). Some of these negative affect symptoms can

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