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、强迫的和过度摄取。长期大量使用酒精(“酗酒”)导致的神经适应被认为是推动这一进程的原因，导致在停止摄入时出现促使复发的负面影响。因此，摄入酒精是因为它的负面强化作用--防止或缓解情绪性戒断症状。时程研究表明，急性和晚期长期戒断是促使饮酒的不同阶段，其神经生物学基础尚不清楚。行为和神经化学数据表明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。目前应用的首要假设是，长期大量使用乙醇会导致焦虑性下丘脑外CRF增加！或Y2信号，并降低了抗焦虑的YI活性，每一种都导致了长期酒精戒断期间的“被动”焦虑行为。特定的目标1将确定长期自我饮酒史是否会导致急性或长期戒酒时焦虑样行为的增加。特定的AIM 2将决定 无论是通过长期被动酒精蒸气暴露还是通过长期自愿酗酒导致酒精依赖的大鼠，在中央延伸的杏仁核或外侧隔区的组件中，CRF、NPY或其同源受体的表达都显示出类似的异常，这些组件是帮助焦虑样行为和酒精强化的大脑区域。利用LC-MS、免疫分析以及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)观察到长时间戒断后焦虑样行为的复发。最后，特定的AIM 3将选择性CRF和NPY受体配体注射到不同的脑区，以确定AIM 2中出现的神经化学变化与长期戒断焦虑增加的功能相关性。

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.