Component 8: Zorrilla

随着酒精依赖的发展，摄入量从受控饮酒转变为不受控制的、强迫的和 摄入过多。长期大量饮酒(“酗酒”)导致的神经适应 假想推动这一进程，导致复发的负面影响的出现 停止摄取。因此，酒精摄入量因其负面强化特性而被迫-- 防止或缓解情绪性戒断症状。时间进程研究表明，急性和迟发性 长期禁欲是刺激饮酒的不同戒断阶段，其神经生物学 其基础仍不明朗。行为和神经化学数据表明调控失调的作用 情感性下丘脑外促肾上腺皮质激素释放因子和神经肽Y的功能 戒断症状。目前应用的首要假设是慢性重乙醇 使用会导致焦虑性下丘脑外CRF增加！或Y2信号，并减少抗焦虑的YI 在长期戒酒期间，每一种活动都会导致“被动”的焦虑行为。 特定的目标1将确定长期自我管理的酗酒史是否会导致 急性或长期戒酒后焦虑样行为增加。特定的AIM 2将决定 无论大鼠是通过慢性被动酒精蒸气暴露还是通过慢性酒精蒸气暴露导致酒精依赖 自愿暴饮者CRF、NPY或其同源受体的表达也出现类似的异常 中央延伸的杏仁核或外侧隔的组成部分，这是大脑中缓解焦虑症的区域 行为和乙醇强化。使用LC-MS，免疫分析，定量和功能 放射自显影技术，研究试图确定哪些神经化学变化与 从早期(2周)到晚期(6-12周)观察到的焦虑样行为的复发持续时间较长 戒烟。最后，特定的AIM 3将选择性CRF和NPY受体配体注射到离散的大脑中 确定在AIM 2中看到的神经化学变化与增加的 对长期戒断的焦虑。相关性：通过增加对急性和慢性阻塞性肺疾病神经生物学的了解 在长期戒断的情况下，这些研究可能会促进预防和缓解 情绪性戒断症状，从而减少继续和恢复饮酒的“需要”。

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. Relevance: By increasing understanding of the neurobiology of acute and protracted withdrawal, the studies may facilitate development of therapeutics that prevent and relieve affective withdrawal symptoms and thereby reduce the "need" to continue and resume drinking ethanol.