Component 8: Zorrilla

随着酒精依赖的发展，摄入量从有控制的饮酒转变为无控制的，强迫性的和过量的摄入。假设由慢性、大量使用乙醇（“暴饮暴食”）引起的神经适应性会推动这种进展，导致停止摄入后出现复发动机的负面影响。因此，酒精的摄入量就不得不发挥其消极的强化作用--以避免或缓解情感性戒断症状。时间进程研究表明，急性和晚期长期禁欲是不同阶段的撤退，激励饮酒和其神经生物学基础尚不清楚。行为学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。本申请的首要假设是长期大量使用乙醇导致焦虑性下丘脑外CRF的增加！或Y2信号传导和抗焦虑Yi活性的降低，其中每一种都有助于延长乙醇戒断期间的“被动”焦虑行为。具体目标1将确定慢性自我管理的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 无论是通过慢性被动乙醇蒸汽暴露还是通过慢性自愿狂饮使大鼠呈现乙醇依赖性，其在中央延伸杏仁核或侧隔的组分中CRF、NPY或其同源受体的表达均显示出类似的异常，所述中央延伸杏仁核或侧隔是有助于焦虑样行为和乙醇强化的脑区域。使用LC-MS、免疫测定以及定量和功能性放射自显影技术，研究试图确定哪些神经化学变化与神经元的功能变化一致。 从早期（2周）到晚期（6-12周）观察到的焦虑样行为的复发。最后，特异性AIM 3将选择性CRF和NPY受体配体微量注射到离散的脑区，以确定AIM 2中观察到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.