As ethanol dependence develops, intake transitions from controlled drinking to uncontrolled, compulsive, andexcessive intake. Neuroadaptations that result from chronic, heavy ethanol use ('binge-like drinking') arehypothesized to drive this progression, leading to the emergence of relapse-motivating negative affect uponcessation of intake. Ethanol intake thereby becomes compelled for its negative reinforcing properties -- toward off or relieve affective withdrawal symptoms. Time course studies suggest that acute and lateprotracted abstinence are distinct stages of withdrawal that motivate drinking and whose neurobiologicalunderpinnings remain unclear. Behavioral and neurochemical data implicate roles for dysregulatedextrahypothalamic corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) function in affectivewithdrawal symptoms. The overarching hypothesis of the present application is that chronic heavy ethanoluse leads to increases in anxiogenic extrahypothalamic CRF! or Y2 signaling and decreases in anxiolytic Yiactivity, each of which contributes to 'passive' anxiety behaviors during protracted ethanol abstinence.
SPECIFIC AIM 1 will determine whether a chronic history of self-administered binge drinking leads toincreased anxiety-like behavior upon acute or protracted ethanol withdrawal.
SPECIFIC AIM 2 will determinewhether rats rendered ethanol dependent via chronic passive ethanol vapor exposure or via chronicvoluntary binge drinking show similar abnormalities in expression of CRF, NPY or their cognate receptors incomponents of the central extended amygdala or lateral septum, brain regions that subserve anxiety-likebehavior and ethanol reinforcement. Using LC-MS, immunoassay, and quantitative and functionalautoradiographic techniques, studies seek to identify which neurochemical changes coincide with theresurgence of anxiety-like behavior observed from early (2 weeks) to late (6-12 weeks) protractedwithdrawal. Finally, SPECIFIC AIM 3 microinjects selective CRF and NPY receptor ligands into discrete brainregions to determine the functional relevance of neurochemical changes seen in AIM 2 for the increasedanxiety of protracted withdrawal. Relevance: By increasing understanding of the neurobiology of acute andprotracted withdrawal, the studies may facilitate development of therapeutics that prevent and relieveaffective withdrawal symptoms and thereby reduce the 'need' to continue and resume drinking ethanol.
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