Preoccupation/Anticipation Stage

Protracted Abstinence

Prolonged abstinence from alcohol in humans involves a residual negative emotional state that can persist for weeks or months after acute withdrawal. To study protracted abstinence in animal models, one can define such a state as spanning a period when acute physical withdrawal has subsided, but behavioral changes persist. Increases in alcohol intake over the pre-dependence baseline and increases in stress responsivity persist for 2–8 weeks post-withdrawal from chronic alcohol. Rats tested 3–5 weeks post-withdrawal in the elevated plus maze, which is commonly used to evaluate anxiety-like behavior in rodents, did not show anxiogenic-like responses at baseline. However, angiogenic-like responses were induced by mild restraint stress only in rats with a history of alcohol dependence. This stress-induced anxiogenic-like response was reversed by a CRF receptor antagonist (Figure 6.22). The increase in alcohol self-administration during protracted abstinence was blocked by CRF antagonists. Similar effects on alcohol self-administration during protracted abstinence have been observed with administration of a glucocorticoid receptor antagonist. Thus, brain CRF systems appear to remain hyperactive during protracted abstinence, and this hyperactivity is motivationally relevant to excessive alcohol drinking. Results such as these suggest that the emotional substrates of the brain that are dysregulated in the binge/intoxication and withdrawal/negative affect stages remain dysregulated and contribute to craving and relapse).

Figure 6.20 (A) Effects of CRF1 receptor small-molecule antagonist R121919 on ethanol self-administration in dependent and nondependent rats. Ethanol dependence was induced by intermittent exposure to ethanol vapors for 4 weeks. Animals were subsequently tested for ethanol and water self-administration following 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals displayed a significant increase in ethanol lever pressing compared with nondependent animals. R121919 significantly decreased ethanol self-administration in withdrawn, dependent but not nondependent animals. Neither ethanol vapor exposure nor R121919 altered water responding. ∗p < 0.001 compared with same drug dose in nondependent animals. #p < 0.0001 compared with vehicle treatment in dependent animals. (B) Effects of CRF1/CRF2 peptide antagonist d-Phe CRF12–41 administered directly into the central nucleus of the amygdala on ethanol and water self-administration in ethanol-dependent and nondependent rats. Ethanol dependence was induced by intermittent exposure to ethanol vapors for 4 weeks. Animals were subsequently tested for ethanol and water self-administration after 2 hours of acute withdrawal. Withdrawn, ethanol-dependent animals displayed a significant increase in ethanol lever pressing compared with nondependent animals. d-Phe CRF12–41 significantly decreased ethanol self-administration in withdrawn, dependent but not nondependent animals when administered directly into the central nucleus of the amygdala. Neither ethanol vapor exposure nor d-Phe CRF12–41 altered water responding. ∗p < 0.0001, compared with same drug dose in nondependent animals. #p < 0.0001, compared with vehicle treatment in dependent animals. Error bars indicate SEM. These data show that systemic administration of the small-molecule CRF1 receptor antagonist or intracerebral injection of a mixed peptide CRF1/CRF2antagonist into the central nucleus of the amygdala selectively blocked only the excessive drinking induced by withdrawal from alcohol in dependent rats using the alcohol vapor procedure. Notice that the CRF antagonists had no effect in nondependent rats with limited access. [Taken with permission from Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biological Psychiatry, 2007, (61), 78–86.] [Taken with permission from Funk CK, O’Dell LE, Crawford EF, Koob GF. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. Journal of Neuroscience, 2006, (26), 11324–11332.].

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