Mifepristone pretreatment reduces ethanol withdrawal severity in vivo.

Stress Often Precedes the development of alcohol dependence and is also a consequence of dependence, thereby perpetuating the cycle of dependence, withdrawal, and relapse to alcohol use (Heilig et al., 2010; Koob and Kreek, 2007). Indeed, many individuals report drinking to overcome negative effect (Addolorato et al., 2005), and it has long been appreciated that ethanol (EtOH) itself can act as a physiological stressor (Ellis, 1966). Work with clinical samples has demonstrated strong correlations between hypothalamic–pituitary–adrenal (HPA) axis disruption and alcohol dependence, craving and relapse to drinking in dependent individuals (Adinoff et al., 2005; O’Malley et al., 2002). Acute alcohol exposure stimulates the release of corticotrophin-releasing factor (CRF), thereby initiating HPA axis activity and subsequently stimulating the synthesis and release of adreno-corticotropin releasing hormone and corticosterone (CORT) (Rivier et al., 1984). Plasma CORT levels have been reported to be either elevated (Rasmussen et al., 2000; Sinha et al., 2009) or reduced (Richardson et al., 2008; Weiss et al., 2001) following prolonged alcohol exposure. Similarly, HPA axis reactivity to subsequent stressors can be either dampened (Adinoff et al., 1998) or elevated (Fox et al., 2009) following a period of alcohol dependence. Factors contributing to these discrepancies in HPA axis activity and CORT concentration following acute or chronic EtOH administration likely include age of the subjects (Klimes-Dougan et al., 2001), sex of the subjects (Handa et al., 1994; Klimes-Dougan et al., 2001; Sinha et al., 2009), differences in diurnal timing of measurement (Klimes-Dougan et al., 2001), prior drug exposure (Sinha et al., 2009), rodent strain (Roberts et al., 1992), alcohol exposure paradigms (Ogilvie et al., 1997; Rasmussen et al., 2000), and the level of alcohol reactivity in individual animals (Richardson et al., 2008). In related findings, it was reported that polymorphisms in glucocorticoid receptors (GRs) (Rosmond et al., 2000) or CRF-1 receptor activity (Clarke et al., 2008) may influence basal CORT, and potentially, EtOH-stimulated CORT secretion. Interestingly, Huizink and colleagues (2006) reported that either elevated or reduced HPA axis activity may be associated with substance abuse disorders. EtOH withdrawal was reported to produce elevations in cortisol secretion during the early withdrawal phase, reaching micromolar concentrations (Esel et al., 2001); these levels moderate with prolonged abstinence in humans (Adinoff et al., 1998; von Bardeleben et al., 1989). In fact, a subset of alcohol-dependent individuals display Cushing’s-like syndrome during active drinking and early withdrawal (Besemer et al., 2011). Interestingly, there may be a correlation between the magnitude of the rise in circulating cortisol and increased severity of alcohol withdrawal (Risher-Flowers et al., 1988). Rasmussen and colleagues (2000) showed chronic EtOH intake, which yielded moderate blood EtOH levels (BELs), is sufficient to produce high concentrations of free CORT during the early stage of withdrawal in rodents. Vendruscolo and colleagues (2012) reported a reduction in GR mRNA during early withdrawal from intermittent EtOH vapor exposure. Similarly, Alele and Devaud (2007) demonstrated that withdrawal from 14 days of exposure to a liquid EtOH diet produced marked elevations in plasma CORT in male, but not female, rats. In vitro studies of rodent, hippocampal explants are consistent with the hypothesis that CORT has a role in promoting neuronal excitation and, possibly, neuronal injury during EtOH withdrawal (Mulholland et al., 2005). As a whole, these findings suggest that hypercortisolemia may contribute to both the development of EtOH dependence and, hence, the severity of EtOH withdrawal. The present studies examined the hypothesis that GR antagonism would attenuate the development of alcohol dependence by administering the GR antagonist mifepristone daily during exposure to a modified 4-day EtOH gavage paradigm, modified after Majchrowicz (1975).