Studies using operant conditioning procedures also have demonstrated an important role for CRF in mediating the ability of stress to trigger relapse-like behavior. For example, CRF antagonists have been shown to block stress-induced reinstatement of alcohol seeking behavior (Gehlert et al., 2007; Le et al., 2000; Liu and Weiss, 2002; Marinelli et al., 2007). This effect appears to be mediated by extra-hypothalamic CRF activity, since adrenalectomy (with or without corticosterone supplementation) did not affect reinstatement of alcohol responding induced by foot-shock stress (Le et al., 2000). In fact, direct infusion of a CRF antagonist into the median raphe nucleus blocked stress-induced alcohol seeking behavior (Funk et al., 2003; Le et al., 2002; Le et al., 2013). CRF1 receptor antagonists injected into the ventral tegmental area reduced alcohol intake in high-drinking models, including stress-enhanced drinking (Hwa et al., 2016; Rinker et al., 2016). Overall, while a role for CRF2 receptors cannot be ruled out (Funk and Koob, 2007; Valdez et al., 2004), the large preponderance of evidence suggests that CRF1 receptors play an important role in regulating alcohol consumption, especially excessive
