Elsevier

Brain Research

Volume 1155, 25 June 2007, Pages 172-178
Brain Research

Research Report
A CRF2 agonist administered into the central nucleus of the amygdala decreases ethanol self-administration in ethanol-dependent rats

https://doi.org/10.1016/j.brainres.2007.04.009Get rights and content

Abstract

Alcohol dependence is characterized by excessive consumption, loss of control over intake and the presence of a withdrawal syndrome, including both motivational and physical symptoms. Previous studies have implicated the brain corticotropin-releasing factor (CRF) stress systems in mediating the negative emotional state associated with ethanol withdrawal. CRF1 receptor-specific antagonists, administered systemically, and CRF receptor subtype nonspecific antagonists, administered into the central nucleus of the amygdala (CeA), selectively decrease the anxiety-like behaviors and increased ethanol self-administration associated with ethanol withdrawal. In the present study, we investigated the role of CRF2 receptors within the CeA in mediating ethanol self-administration in ethanol-dependent and nondependent animals. Male Wistar rats were made dependent on ethanol using an intermittent ethanol vapor exposure paradigm. Nondependent animals received similar conditions but were exposed to air only. Following 2 h of withdrawal from ethanol vapors, ethanol and water self-administration were measured following administration of urocortin 3, a highly selective CRF2 agonist, in the CeA. In dependent rats, urocortin 3 (0.1 μg/μl and 0.5 μg/μl) decreased ethanol self-administration, with no effect on water self-administration. In nondependent rats, urocortin 3 (0.5 μg/μl) increased ethanol self-administration, with no effect on water self-administration. These data demonstrate an opposing role of the CRF2 receptor subtype within the CeA in mediating ethanol self-administration in withdrawn, dependent and nondependent rats.

Introduction

Alcoholism is a chronic relapsing disorder characterized by a compulsive use of alcohol and a loss of control over intake. As dependence develops, there is a shift from controlled use to uncontrolled, excessive consumption of alcohol, which has been argued to be a shift from positive to negative reinforcement ultimately driving continued alcohol use (Koob, 2003, Koob et al., 2004). Cessation of chronic alcohol use often is accompanied by negative emotional symptoms, such as increased anxiety. Alleviation of these negative emotional states is hypothesized to be a major force driving continued alcohol consumption (Hershon, 1977, Koob, 2003). Understanding the brain systems underlying these withdrawal-induced behaviors is an important step toward the development of novel pharmacotherapies for the treatment of alcohol dependence.

Ethanol-dependent rats also display enhanced anxiety-like behaviors and excessive ethanol self-administration during periods of withdrawal (Roberts et al., 2000, Rasmussen et al., 2001, Overstreet et al., 2002, Rimondini et al., 2002, Becker and Lopez, 2004, O'Dell et al., 2004). Multiple studies have implicated the brain corticotropin-releasing factor (CRF) stress system in mediating the motivational changes associated with dependence (Menzaghi et al., 1994, Valdez and Koob, 2004). CRF, a 41 amino-acid peptide residue involved in mediating the physiological and behavioral responses to stress, is distributed throughout the brain, with high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus and in areas of the extended amygdala (Vale et al., 1981, Bloom et al., 1982, Dunn and Berridge, 1990). During ethanol withdrawal in dependent rats there is an increase in extracellular CRF within the extended amygdala, specifically within the central nucleus of the amygdala (CeA) (Merlo Pich et al., 1995). Administration of CRF antagonists within the CeA attenuates the enhanced anxiety-like behaviors and increased ethanol self-administration associated with withdrawal (Rassnick et al., 1993, Funk et al., 2006) suggesting an important role of CRF within this brain region in mediating ethanol dependence. Further, lesions of the CeA reduce anxiogenic-like behaviors resulting from restraint stress and reduce voluntary ethanol intake (Moller et al., 1997), demonstrating the importance of this brain region in mediating anxiety and ethanol consumption.

Within the brain, the cellular effects of CRF are mediated by two subtypes of high affinity receptors, CRF1 and CRF2 (Vale et al., 1981, Bloom et al., 1982, Dunn and Berridge, 1990, Chang et al., 1993, Chen et al., 1993, Perrin et al., 1993, Lovenberg et al., 1995). Previous studies have demonstrated that CRF1 antagonists, administered systemically, reduce ethanol self-administration in ethanol-dependent animals (Funk et al., 2007); effects likely mediated within the CeA (Funk et al., 2006). Interestingly, studies have demonstrated an opposing role for the CRF2 receptor subtype in mediating ethanol withdrawal-induced behaviors (i.e., activation of CRF2 receptors decreases both the enhanced anxiety-like behavior and ethanol self-administration in withdrawn, dependent rats when administered intracerebroventricularly (i.c.v.) (Valdez et al., 2004). Thus, in the present study we tested the hypothesis that CRF2 receptors within the CeA may also mediate excessive ethanol self-administration in withdrawn, ethanol-dependent and nondependent rats.

Section snippets

Effects of the CRF2-specific agonist Ucn 3 on ethanol and water self-administration in dependent and nondependent rats

For the ethanol-dependent group (n = 8), animal weights at the end of the experiment were 560.3 ± 36.5 grams. For the nondependent group (n = 7), animal weights were 603.2 ± 54.9 grams. The mean BAL across the entire period of ethanol vapor exposure was 193 ± 31.7 mg%. Fig. 1 shows the effects of Ucn 3 (0.0, 0.02, 0.1 and 0.5 μg/μl) on ethanol and water self-administration in dependent versus nondependent animals.

In the 30-min test session, following vehicle injection (0.5× PBS), the dependent animals

Discussion

A negative emotional state, especially enhanced anxiety and stress, experienced during ethanol withdrawal is a main factor eliciting relapse and binge drinking during periods of abstinence (Hershon, 1977). In humans alcoholics, anxiety has been shown to persist for up to 9 months, and in some cases for several years, post-withdrawal (Roelofs, 1985). Animal models for ethanol dependence have been developed which mimic excessive drinking and anxiety-like behaviors during withdrawal (Roberts et

Animals

Eighteen adult male Wistar rats weighing 180–200 grams at the start of the experiment were obtained from Charles River Laboratory (Kingston, NY). Animals were housed two to three per cage with food and water available ad libitum. Lights were on a 12-h light/dark cycle, with lights on at 8:00 PM. All procedures met the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Drugs

Ethanol (10% w/v), for oral self-administration, was prepared using 95% ethyl

Acknowledgments

This is publication number 18728 from The Scripps Research Institute. Research was supported by the Pearson Center for Alcoholism and Addiction Research and National Institutes of Health grants AA12602 (GFK) and AA015239 (CKF) from the National Institute on Alcohol Abuse and Alcoholism. We thank Dr. Eric Zorrilla for his insightful comments on the manuscript. The authors also would like to thank Mike Arends for his editorial assistance and Maury Cole for technical assistance. We thank Jean

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