Neuroadaptive changes induced by chronic ethanol have been implicated in symptoms of protracted withdrawal, and relapse risk during abstinence. Studies during the previous funding by this lab and other groups at the TSRI Alcohol Research Center suggest that dysregulation of extrahypothalamic corticotropin-releasing factor (CRF) systems that mediate behavioral and emotional responses to stress may be a neuroadaptive consequence of chronic ethanol use that contributes importantly to affective changes and ethanol-seeking behavior during acute and protracted withdrawal. The present proposal is designed to extend these studies to a systematic multidisciplinary investigation of functional abnormalities in extra hypothalamic CRF systems at different stages of ethanol withdrawal, and to establish the behavioral significance of these changes. The experimental plan is to first characterize the nature and time course of ethanol-related behaviors and their modification by stress over a 12-week withdrawal period. Subsequent studies will determine whether behavioral changes identified in these experiments coincide with specific abnormalities in pre or postsynaptic CRF function in the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Finally, the relevance of functional abnormalities in these CRF systems for behavioral changes that accompany protracted ethanol withdrawal will be confirmed using site-specific administration of CRF-R1 and CRF-R2 receptor antagonists and manipulation of CRF receptor expression by targeted viral vector approaches. The experiments will be guided by the hypothesis that ethanol self-administration, ethanol-seeking behavior, anxiety-like behavior, as well as the augmentation of these behaviors by stress will be greater in rats with a history of dependence than in nondependent rats. Moreover, it is expected (a) that behavioral differences between non-dependent and post-dependent rats will be related to differences in CRF function within the CeA and/or BNST, and (b) that some predictive relationship exists between time-dependent changes in ethanol-related behaviors over course of protracted withdrawal and specific alterations in CRF function in the CeA and/or BNST. A final prediction is that the exacerbation of anxiety, ethanol-seeking and intake in postdependent rats is sensitive to modification by manipulation of CRF neurotransmission in the CeA or BNST. By increasing understanding of the neurobiological basis of acute and protracted withdrawal, these studies are expected to have direct implications for the development of pharmacotherapeutic treatment strategies for the prevention of ethanol-seeking behavior and relapse at different stages of withdrawal and abstinence.
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