Elsevier

Alcohol

Volume 29, Issue 2, February 2003, Pages 55-60
Alcohol

High-priority communication
High-priority communication I Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence

https://doi.org/10.1016/S0741-8329(03)00020-XGet rights and content

Abstract

One of the most critical attributes of chronic abstinence from alcohol is a state of anxiety, which can lead to mood disturbances and negative affect that can last for months or even years in alcoholics. Within hours after their final exposure to ethanol in experimental conditions, laboratory animals also exhibit an anxiety-like state. This state is accompanied by an enhanced stress response and can persist for weeks after withdrawal. One possible mechanism underlying these behavioral changes observed weeks after withdrawal is increased corticotropin-releasing factor (CRF) activity. In the present study, we sought to examine the role of CRF in the regulation of behavior in the elevated plus-maze during protracted abstinence by using intracerebroventricular administration of the CRF receptor antagonist [d-Phe12,Nle21,38,CαMeLeu37]rCRF(12–41) (d-Phe-CRF(12–41)). Rats were surgically implanted with a guide cannula aimed at the lateral ventricles and subsequently fed a nutritionally complete ethanol [10% (vol./vol.)] or control liquid diet for 21 days. Rats were further divided into groups receiving microinjections of d-Phe-CRF(12–41) or vehicle and 15 min of restraint stress, or d-Phe-CRF(12–41) or vehicle and no restraint. Six weeks after removal of the liquid diet, rats were injected and then placed in a restraint tube or returned to their home cages for 15 min before testing in the elevated plus-maze. Rats with a history of ethanol dependence explored the open arms of the plus-maze significantly less when exposed to restraint stress compared with findings for all other groups, an effect attenuated by pretreatment with d-Phe-CRF(12–41). Results of the current experiment demonstrated that continuous exposure to ethanol over a 3-week period leads to an increased behavioral responsiveness to stress, which seems to be regulated by CRF.

Introduction

Negative emotional states have been hypothesized to be a defining characteristic of abstinence in alcohol-dependent individuals. One of the most critical attributes of chronic abstinence (i.e., abstinence from heavy alcohol use for long periods) is a state of anxiety, during which alcoholics experience mood disturbances and negative affect (Begleiter and Porjesz, 1979, Grant et al., 1987, Roelofs, 1985), which have been shown to be correlated with relapse (Annis et al., 1998, Hershon, 1977). These alterations in mood can be long-lasting in nature, as abstinent alcoholics show symptoms of anxiety for months and even years after their last drink (De Soto et al., 1985, Roelofs, 1985).

In experimental conditions, laboratory animals with a history of ethanol dependence also exhibit an anxiety-like state, during which an enhanced stress response is experienced (Hölter et al., 1998, Möller et al., 1997, Rassnick et al., 1993). This stress response can last for weeks after withdrawal (Rasmussen et al., 2001). For example, ethanol-dependent rats display significantly less gnawing behavior when examined in the novel cork gnawing test up to 4 weeks after withdrawal (Rasmussen et al., 2001). Decreased cork gnawing has been proposed as indicative of an increased anxiety-like state (Pollard & Howard, 1990). Rats with a history of ethanol dependence also show a trend toward decreased exploration of the open arms of the elevated plus-maze 4 weeks after withdrawal (Rasmussen et al., 2001), which has been proposed as a risk factor for ethanol drinking in rats (Mormede et al., 1998). Finally, these same rats show increased locomotor activity when placed in a novel environment (Rasmussen et al., 2001). This observation appears to concur with the increased novelty-seeking behavior characteristic of type II alcoholism (Cloninger, 1987).

Although these long-term behavioral changes persist in experimental animals for weeks after chronic ethanol exposure (i.e., continuous exposure to ethanol up to 4 weeks), the underlying neural substrate responsible for such behavioral changes remains unclear. One possible mechanism is corticotropin-releasing factor (CRF), a 41–amino acid neuropeptide involved in mediating neuroendocrine (Vale et al., 1981), autonomic (Dunn and Berridge, 1990, Vale et al., 1983), and behavioral (Koob et al., 1994, Koob and Heinrichs, 1999) responses to stress. Centrally administered CRF potentiates the locomotor-activating effects of acute withdrawal from chronic ethanol exposure (Ehlers & Chaplin, 1987). In addition, rats display a significant decrease in open arm exploration in the elevated plus-maze during acute withdrawal (i.e., within 24 h after their final exposure to ethanol), an effect attenuated by CRF receptor antagonism (Baldwin et al., 1991, Rassnick et al., 1993). Results of in vivo microdialysis studies show increased release of CRF in the amygdala during acute withdrawal (Merlo-Pich et al., 1995, Richter and Weiss, 1999).

These acute changes observed in CRF systems may be much longer lasting, as chronic ethanol exposure can increase electroencephalogram responsiveness to CRF in the cortex up to 15 weeks after withdrawal (Slawecki et al., 1999). In addition, chronic ethanol consumption can increase CRF-like immunoreactivity in the amygdala up to 6 weeks after withdrawal (Zorrilla et al., 2001), perhaps contributing to an increased behavioral responsiveness to stress. In the current study, we sought to test the hypothesis that increased CRF levels can lead to an enhanced responsiveness to stress during protracted abstinence by examining the regulation of behavior in the elevated plus-maze after intracerebroventricular administration of a competitive CRF receptor antagonist.

Section snippets

Animals

Male Wistar rats (Charles River, Kingston, NY; n = 66) were used in this experiment. Individual body weight ranged between 200 and 250 g at the start of the experiments. Rats were handled daily for 5 days before the start of the experiments. Rats were group housed (three per cage) with food and water available ad libitum except during liquid diet administration. Rats were maintained on a 12-h/12-h light/dark cycle (lights on at 2200). Procedures met the guidelines of the National Institute on

Results

The mean blood ethanol level across the entire period of liquid diet administration was 132.3±24.7 mg%. Restraint decreased the percentage of time spent in the open arms in rats that were fed an ethanol diet, indicated by a significant diet×stressor interaction [F(1, 57) = 4.9, P<.05] (Fig. 1). Ethanol-dependent rats displayed a lower percentage of time exploring the open arms of the plus-maze when exposed to restraint, an effect attenuated by pretreatment with 10 μg of d-Phe-CRF(12–41) (P<.05).

Discussion

The findings of the present experiment demonstrated that chronic ethanol exposure leads to an increased responsiveness to restraint stress in rats tested during protracted abstinence. With the use of a previously described model of protracted ethanol abstinence (Zorrilla et al., 2001), rats tested in the elevated plus-maze displayed a decreased preference for open arm exploration when exposed to 15 min of restraint stress. This response seems to be regulated by CRF, as injection of the

Acknowledgments

Support was provided by AA08459 from the National Institute on Alcohol Abuse and Alcoholism (GFK). GRV was supported by an Individual National Research Service Award AA05563 from the National Institute on Alcohol Abuse and Alcoholism. EPZ was supported by a Minority Research Supplement to DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. We gratefully recognize the editorial assistance of Mike Arends. We would also like to thank Dr. Jean Rivier of The Salk

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