Effects of Drug Withdrawal on CRF Levels in the Amygdala

Substantial evidence now suggests that brain extrahypothalamic CRF systems are activated during the development of dependence on alcohol, and this activation has motivational significance. During ethanol withdrawal, CRF release increases 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) (Figures 1B and ​and2),2), and this dysregulation of brain CRF systems is hypothesized to underlie both the enhanced anxiety-like behaviors and enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, systemic CRF₁ antagonists (Overstreet et al., 2004) or the subtype nonselective CRF receptor antagonists α-helical CRF_9-41 and D-Phe CRF_12-41 when injected intracerebroventricularly (Baldwin et al., 1991) or directly into the central nucleus of the amygdala (Rassnick et al., 1993) reduced ethanol withdrawal-induced anxiety-like behavior.

Exposure to repeated cycles of chronic ethanol vapor to induce dependence substantially increased ethanol intake in rats, both during acute withdrawal and during protracted abstinence (2 weeks postacute withdrawal) (O?Dell et al., 2004; Rimondini et al., 2002). Intracerebroventricular administration and direct intracerebral administration into the central nucleus of the amygdala of a CRF₁/CRF₂ peptide antagonist selectively blocked the dependence-induced increase in ethanol self-administration during acute withdrawal (Valdez et al., 2004). Systemic injections of small-molecule CRF₁ antagonists also blocked the increased ethanol intake associated with acute ethanol withdrawal (Knapp et al., 2004; Funk et al., 2007; Richardson et al., 2008) (Figure 3). A CRF₂ agonist injected into the central nucleus of the amygdala had a similar effect in reducing the increase in ethanol self-administration associated with acute withdrawal, suggesting a role for CRF₂ receptors opposite to that of CRF₁ receptors in modulating ethanol intake in dependent animals (Funk and Koob, 2007). CRF antagonists injected intracerebroventricularly or systemically also blocked the potentiated anxiety-like responses to stressors observed during protracted abstinence (Breese et al., 2005; Valdez et al., 2003) and the increased ethanol self-administration associated with protracted abstinence (Valdez et al., 2004; Funk et al., 2006). None of the CRF antagonists had any effects on ethanol self-administration in nondependent rats (Valdez et al., 2004). These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence.

Figure 3

Date: 2016-06-12; view: 258