Chunk #41 — 3 Neural Substrates for the Negative Emotional State Associated with Alcoholism — 3.2 Between-System Neuroadaptations that Contribute to Compulsivity Associated with the Dark Side of Alcoholism
The ability of CRF antagonists to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal would predict motivational effects of CRF antagonists in animal models of extended access to drugs. 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 in 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 subtype nonselective CRF receptor antagonists α-helical CRF9–41 and D-Phe CRF12–41 (intracerebroventricular administration) reduced ethanol self-administration in dependent animals during acute withdrawal and during protracted abstinence (Valdez et al. 2002). When administered directly into the central nucleus of the amygdala, a CRF1/CRF2 antagonist blocked ethanol self-administration in ethanol-dependent rats (Funk et al. 2006).
