The CRF-1 receptor antagonist, CP-154,526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice

Stress may be a key contributor to the development of ethanol dependence and relapse (Breese et al., 2005; Koob, 2003). Stressful life events, such as those underlying post-traumatic stress disorder, are comorbid with ethanol abuse disorders and human laboratory studies show that stress increases the self-report of craving in abstinent alcoholics (Back et al., 2006; Breslau et al., 2003; Fox et al., 2007). Clinical research implicates stress in the relapse to pathological ethanol use in formerly abstinent alcoholics, perhaps as a means to self-medicate heightened anxiety and negative affect associated with withdrawal and abstinence from alcohol (Brady and Sonne, 1999; Breese et al., 2005; Kushner et al., 1994; Sinha, 2001). Recent investigations show that stress can also impact ethanol consumption in animal models (Chester et al., 2004; Croft et al., 2005; Le et al., 2000; Little et al., 1999; Liu and Weiss, 2002; Sillaber et al., 2002). Various stress paradigms reliably elicit stress-induced increases in ethanol consumption, especially among low ethanol consuming animals (Chester et al., 2004; Croft et al., 2005; Little et al., 1999). For example, selectively bred ethanol non-preferring NP rats exposed to 10 days of restraint stress showed significant and enduring increases in ethanol consumption beginning approximately 2 weeks following the stress procedure, while ethanol preferring P rats showed only transient stress-induced increases in ethanol drinking immediately after the stress procedure (Chester et al., 2004). Additionally, 3 weeks of stress induced by daily saline injections (Little et al., 1999) or 5 consecutive days of social defeat stress (Croft et al., 2005), significantly increased ethanol consumption approximately 2 weeks after the stress procedure among C57BL/10 mice displaying initially low preference for ethanol. An interesting commonality among many animal studies that assess the effects of stress on ethanol intake is that the effects of stress on ethanol drinking are delayed, typically occurring weeks after stress exposure (Chester et al., 2004; Croft et al., 2005; Little et al., 1999). Both ethanol and stress activate the hypothalamic-pituitary-adrenal (HPA) axis by inducing the release of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and glucocorticoids (Brady and Sonne, 1999). The relationship between ethanol and the HPA-axis appears to be bidirectional, as exogenous administration of CRF, ACTH, and glucocorticoids alter ethanol consumption (Bell et al., 1998; O’Callaghan et al., 2002; Thorsell et al., 2005). Given that neurobiological responses to both stress and ethanol exposure involve HPA-axis signaling, it is possible that the neurochemicals and hormones associated with the HPA-axis modulate stress-induced increases of ethanol consumption. One such candidate is CRF, a 41 amino acid polypeptide that integrates both neuroendocrine and behavioral responses to stress (Smith et al., 1998). CRF-containing neurons are expressed throughout the brain, including in regions implicated in neurobiological responses to ethanol such as the bed nucleus of the stria terminalis, the amygdala, and the lateral hypothalamus (Koob, 2003). Of the two G protein-coupled receptors, the CRF1 receptor (CRF1R) appears to be involved with the integrate emotional behavior while the CRF2 receptor (CRF2R) may modulate ingestive behaviors (Koob, 2003; Zorrilla and Koob, 2004; Zorrilla et al., 2004). Corticotropin-releasing factor receptor signaling has been implicated in a variety of neurobiological responses to ethanol. For example, CRF receptor antagonists attenuate the anxiogenic effect of ethanol withdrawal (Breese et al., 2004; Knapp et al., 2004; Overstreet et al., 2004; Rassnick et al., 1993), prevent excessive ethanol self-administration in dependent animals (Funk et al., 2007; Valdez et al., 2002), and block foot shock-induced reinstatement of ethanol-seeking behavior (Liu and Weiss, 2002). The CRF1R also appears to be involved in stress-induced increases in ethanol consumption. Mutant mice lacking normal production of the CRF1R displayed significantly greater ethanol consumption beginning approximately 2 weeks after a social defeat stress procedure, an effect that was not evident in normal wild-type mice. Subsequent exposure to forced swim stress further augmented ethanol consumption in CRF1R knockout mice (Sillaber et al., 2002). While the Sillaber et al. (2002) study provides genetic evidence suggesting a role for the CRF1R in modulating stress-induced increases in ethanol consumption, the goal of the present experiment was to use a pharmacological approach to determine if pretreatment with the selective CRF1R antagonist, CP-154,526, would buffer the effects of stress and thus attenuate the development of stress-induced increases in ethanol intake in BALB/cJ mice. Therefore, we predicted that (1) ethanol consumption would increase among animals with a history of stress exposure and (2) pretreatment with CP-154,526 would attenuate stress-induced increases in ethanol consumption among animals with a history of stress. BALB/cJ mice were chosen because this strain has been shown to have high sensitivity to the effects of stress on both behavioral and neurobiological measures (Crawley et al., 1997) and drinks low levels of ethanol (Belknap et al., 1993). We also assessed the effects of stress exposure on ethanol consumption by C57BL/6N mice, a strain that voluntarily consumes high amounts of ethanol (Belknap et al., 1993). Here we show that 5 consecutive days of exposure to a 5-minute forced swim stress procedure caused significant and delayed increases in voluntary ethanol consumption in BALB/cJ mice, an effect which was attenuated by pretreatments with the CRF1R antagonist before each stress session. On the other hand, stress exposure did not alter ethanol intake by C57BL/6N mice.