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耗的神经生物学反应。通过Y1受体传递NPY信号是限制乙醇摄入的一种机制。中枢NPY的表达是由camp依赖性蛋白激酶（PKA）活性驱动的，抑制PKA活性的操作会降低NPY水平并增加乙醇饮用量。由于NPY和促肾上腺皮质激素释放因子（CRF）的作用相反，因此有研究表明，NPY和促肾上腺皮质激素释放因子（CRF）通过扩展的杏仁核内的非稳态相互作用相互调节药物自我给药。因此，当NPY限制乙醇摄入时，CRF活性增加了乙醇消耗的可能性。异稳态模型表明，由反复戒酒和复发引起的不受控制的乙醇饮酒是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NPY信号通过CRF的相互调节来防止乙醇摄入增加的指导性假设。具体的实验将解决以下问题：(A)延长杏仁核中NPY的长期体内过度表达是否会通过Y1受体信号减少自愿乙醇摄入？这些研究将评估小鼠在用重组腺相关病毒（rAAV）载体进行位点定向转导后自愿消耗乙醇，该载体可引起NPY的表达和组成性分泌（rAAV- fib -NPY）。(B)自愿乙醇摄入量增加与NPY Y1受体信号传导减少相关是否源于CRF活性不调节？这些研究将评估长期服用CRF受体拮抗剂后Y1受体缺陷小鼠的乙醇消耗量。(C)体内长期过度表达NPY或长期使用CRF受体拮抗剂是否会限制酒精剥夺效应（ADE）和应激刺激导致的不受控制的酒精饮酒的发展？(D)为了确定低NPY信号传导是否会推广到另一个高乙醇消耗的既定模型，研究将评估缺乏PKA Rllbeta亚基的突变小鼠是否如最近证据所预测的那样，在扩展的杏仁核中具有低NPY表达。这些研究将对NPY信号在酒精消耗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.