primary disorder (Hettema et al., 2003). Dysregulation of the brain CRH system (innate or resulting as a maladaptive response to drugs of abuse or stress) appears to be one of the major elements common to depression, anxiety and addiction (see for review Nemeroff et al., 2005). Preclinical studies have shown that physical, social, and emotional stress can facilitate acquisition or increase self-administration of ethanol in rodents and nonhuman primates (Mollenauer et al., 1993; Higley et al., 1991) and can elicit reinstatement of extinguished ethanol-seeking behavior in drug-free animals (Martin-Fardon et al., 2000; Le et al., 2000). These effects appear to be predominantly controlled by the extrahypothalamic CRH-R1 system. For example, it has been recently demonstrated that administration of various structurally-unrelated, selective CRH-R1 antagonists markedly reduces ethanol self-administration in animals with a history of alcohol dependence (Funk et al., 2006) and the central nucleus of the amygdala (CeA) has been shown to be the brain site of action of these compounds (Funk et al., 2006). The role of extrahypothalamic CRH1R in mediating the reinstatement of alcohol seeking behavior has also been demonstrated. For example, foot shock stress-induced reinstatement of extinguished ethanol responding is reversed by pretreatment with selective CRH antagonists but
