A particularly dramatic example of the motivational effects of CRF in dependence can be observed in animal models of ethanol self-administration in dependent animals. During ethanol withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002). The dysregulation of brain CRF systems is hypothesized to underlie not only the enhanced anxiety-like behaviors but also the enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, the -helical CRF9–41 and D-Phe CRF12–41 (intracerebroventricular administration) reduce ethanol self-administration in dependent animals (Valdez et al., 2004). Exposure to repeated cycles of chronic ethanol vapor produced substantial increases in ethanol intake in rats both during acute withdrawal and during protracted abstinence (2 weeks post-acute withdrawal) (O’Dell et al., 2004; Rimondini et al., 2002). Intracerebroventricular administration of a CRF1/CRF2 antagonist blocked the dependence-induced increase in ethanol self-administration during both acute withdrawal and protracted abstinence (Valdez et al., 2004). When administered directly into the central
