Neuropeptide Y: Role in Ethanol Intake and Sensitivity

描述(由申请人提供)：过去几年的研究表明，NPY信号调节对乙醇和乙醇消费的神经生物学反应。通过Y1受体的NPY信号是限制酒精摄入量的一种机制。中枢NPY的表达是由cAMP依赖的蛋白激酶(PKA)活性驱动的，抑制PKA活性的操作会降低NPY水平并增加饮酒量。由于NPY和促肾上腺皮质激素释放因子(CRF)的作用相反，它们通过杏仁核内的变态反应相互调节药物的自我给药。因此，虽然NPY限制乙醇摄入量，但CRF活性增加了乙醇摄入的可能性。等位模型表明，由于反复禁欲和复发而导致的不受控制的饮酒行为，是NPY系统减弱和CRF系统过度活跃的结果。因此，下面提出的具体目标将检验指导性假设，即NPY信号通过CRF的相互调节，防止乙醇摄入量增加。具体的实验将解决以下问题：(A)在延长的杏仁核中NPY的长期体内过度表达是否会通过Y1受体信号减少自愿酒精摄入？这些研究将评估通过重组腺相关病毒(RAAV)载体进行定点转导后小鼠自愿消耗乙醇的情况，重组腺相关病毒载体可导致NPY的表达和结构性分泌(rAAV-FIB-NPY)。(B)自愿酒精摄入量的增加与NPY Y1受体信号的减少是否源于未受调控的CRF活动？这些研究将评估长期服用CRF受体拮抗剂后Y1受体缺陷小鼠的酒精消耗。(C)长期体内NPY的过度表达或CRF受体拮抗剂的长期应用是否会限制由于酒精剥夺效应(ADE)和暴露于应激刺激而导致的无节制饮酒的发展？(D)为了确定低NPY信号是否会推广到另一个已建立的高酒精消耗模型，研究将评估缺乏PKA Rllbeta亚单位的突变小鼠是否如最近证据所预测的那样，在扩展的杏仁核中有低NPY表达。这些研究将为了解NPY信号在酒精消费和依赖中的作用提供重要的见解。

DESCRIPTION (provided by applicant): Research over the last several years demonstrates that NPY signaling modulates neurobiological responses to ethanol and ethanol consumption. NPY signaling via the Y1 receptor serves as a mechanism to limit ethanol intake. Central NPY expression is driven by cAMP-dependent protein kinase (PKA) activity, and manipulations that inhibit PKA activity decrease NPY levels and increase ethanol drinking. Because of their opposing actions, it has been suggested that NPY and corticotropin releasing factor (CRF) reciprocally regulate drug self-administration through allostatic interactions within the extended amygdala. Thus, while NPY limits ethanol intake, CRF activity increases the likelihood of ethanol consumption. The allostasis model suggests that uncontrolled ethanol drinking stemming from repeated abstinence and relapse evolves as a consequence of a weakened NPY system and a hyperactive CRF system. Hence, the specific aims proposed below will test the guiding hypothesis that NPY signaling, via a reciprocal regulation of CRF, protects against increased ethanol intake. Specific experiments will address the following questions: (A) Will long-term in vivo overexpression of NPY in the extended amygdala reduce voluntary ethanol intake via Y1 receptor signaling? These studies will assess voluntary consumption of ethanol by mice following site-directed transduction with a recombinant adeno-associated virus (rAAV) vector that causes expression and constitutive secretion of NPY (rAAV-FIB-NPY). (B) Does increased voluntary ethanol intake associated with reduced NPY Y1 receptor signaling stem from unregulated CRF activity? These studies will assess ethanol consumption by Y1 receptor deficient mice following chronic administration of a CRF receptor antagonist. (C) Will long-term in vivo overexpression of NPY or chronic application of a CRF receptor antagonist limit the development of uncontrolled ethanol drinking resulting from the alcohol deprivation effect (ADE) and exposure to stressful stimuli? (D) To determine if low NPY signaling generalizes to another established model of high ethanol consumption, studies will assess whether mutant mice that lack the Rllbeta subunit of PKA have low NPY expression in the extended amygdala as predicted by recent evidence. These studies will provide important insight into the role of NPY signaling in alcohol consumption and dependence.