Component 8: Zorrilla

随着乙醇依赖的发展，摄入从控制饮酒转变为不受控制的、强迫性的和过量的摄入。长期大量使用乙醇（“狂饮”）导致的神经适应被认为会推动这种进展，导致在停止摄入时出现复发性的负面影响。因此，酒精的摄入因其负强化特性而变得强制性，以避免或缓解情感性戒断症状。时间进程研究表明，急性和晚期持久戒酒是不同的戒酒阶段，它们会激发饮酒，其神经生物学基础尚不清楚。行为和神经化学数据暗示下丘脑外促肾上腺皮质激素释放因子（CRF）和神经肽Y （NPY）功能失调在情感性戒断症状中的作用。当前应用的首要假设是，长期大量使用乙醇导致下丘脑外焦虑性CRF增加！或Y2信号和抗焦虑Yi活性的降低，这些都有助于长期酒精戒断期间的“被动”焦虑行为。特定目的1将确定慢性自我酗酒史是否会导致急性或长期乙醇戒断后焦虑样行为的增加。具体目标2将决定

As ethanol dependence develops, intake transitions from controlled drinking to uncontrolled, compulsive, and excessive intake. Neuroadaptations that result from chronic, heavy ethanol use ("binge-like drinking") are hypothesized to drive this progression, leading to the emergence of relapse-motivating negative affect upon cessation of intake. Ethanol intake thereby becomes compelled for its negative reinforcing properties -- to ward off or relieve affective withdrawal symptoms. Time course studies suggest that acute and late protracted abstinence are distinct stages of withdrawal that motivate drinking and whose neurobiological underpinnings remain unclear. Behavioral and neurochemical data implicate roles for dysregulated extrahypothalamic corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) function in affective withdrawal symptoms. The overarching hypothesis of the present application is that chronic heavy ethanol use leads to increases in anxiogenic extrahypothalamic CRF! or Y2 signaling and decreases in anxiolytic Yi activity, 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 to increased anxiety-like behavior upon acute or protracted ethanol withdrawal. SPECIFIC AIM 2 will determine whether rats rendered ethanol dependent via chronic passive ethanol vapor exposure or via chronic voluntary binge drinking show similar abnormalities in expression of CRF, NPY or their cognate receptors in components of the central extended amygdala or lateral septum, brain regions that subserve anxiety-like behavior and ethanol reinforcement. Using LC-MS, immunoassay, and quantitative and functional autoradiographic techniques, studies seek to identify which neurochemical changes coincide with the resurgence of anxiety-like behavior observed from early (2 weeks) to late (6-12 weeks) protracted withdrawal. Finally, SPECIFIC AIM 3 microinjects selective CRF and NPY receptor ligands into discrete brain regions to determine the functional relevance of neurochemical changes seen in AIM 2 for the increased anxiety of protracted withdrawal.