Neuropeptide Y: Role in Ethanol Intake and Sensitivity

描述（由申请人提供）：酒精中毒和戒酒者的复发是世界范围内的主要健康问题，目前正在进行研究，以确定这些疾病的潜在药物治疗。然而，非依赖性个人的重度饮酒和酗酒问题受到的关注要少得多。美国国家酒精滥用和酒精中毒研究所（NIAAA）将“狂欢”定义为在短时间内产生血液酒精浓度（BAC）大于0.08%（80 mg/dL）的饮酒模式。频繁的酗酒与许多负面后果有关，包括患情绪障碍、高血压和心脏病以及2型糖尿病的可能性增加。最令人担忧的是，经常酗酒会显著增加人们患酒精依赖症的风险。因此，确定大脑中调节酗酒的神经化学途径至关重要，因为这些知识将为预防这种危险行为的新型药物治疗提供见解。神经肽Y（NPY）在涉及对酒精的神经生物学反应的脑区域中表达，并且NPY防止与依赖相关的过量酒精摄入。因此，我们最近研究了神经肽Y受体信号在狂饮样饮酒中的作用。NPY的中枢给药显著减弱了酗酒样饮酒（在没有NPY的情况下达到BAC>100 mg/dL的小鼠中），但没有减少中等消费水平的小鼠（与BAC <25 mg/dL相关）的饮酒。神经肽Y对狂饮样饮酒的影响是由Y1 R和Y2 R（而不是Y 5 R）受体调节的。重要的是，我们的初步观察还表明，暴饮暴食与杏仁核中央核（CeA）和终纹床核（BNST）的NPY免疫反应性显着降低。因此，本研究的指导性假设是，NPY信号调节酒精的摄入.拟议的目标将使用强大的和创新的电生理，组织学，（免疫反应性），遗传（实时PCR）和解剖学（NPY信号传导的定点操纵）技术来确定是否：A）类似狂饮的饮酒将与NPY表达和受体信号的改变相关，这些变化随着反复的类似狂饮的发作而变得僵硬。（目的1和3），B）扩展杏仁核内的NPY受体信号传导调节狂欢样饮酒（目的2），和C）触发钝化的NPY信号传导和激发狂欢样饮酒的机制涉及表观遗传元件，特别是组蛋白乙酰化的改变（目的2）。目前项目的预期结果将确定Y1 R激动剂，Y2 R拮抗剂和增加组蛋白乙酰化的化合物作为治疗酗酒的有吸引力的靶点。用于抑制和/或预防酗酒的药物干预措施不仅可以帮助个人避免与经常酗酒相关的许多危险的健康后果，而且可以保护易受伤害的个人免于发展到酒精依赖的程度。

DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood alcohol concentrations (BACs) greater than 0.08% (80 mg/dL) within a short period of time. Frequent binge drinking has been linked to numerous negative consequences, including an increased likelihood of developing mood disorders, high blood pressure and heart disease, and type-2 diabetes. Of greatest concern, regular binge drinking significantly increases ones risk of developing alcohol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. Neuropeptide Y (NPY) is expressed in brain regions implicated in neurobiological responses to alcohol and NPY protects against excessive alcohol intake associated with dependence. Thus, we recently studied the role of NPY receptor signaling in binge-like drinking. Central administration of NPY significantly blunted binge-like alcohol drinking (in mice that achieved BACs of >100 mg/dL in the absence of NPY) but did not decrease drinking in mice with moderate levels of consumption (associated with BACs of <25 mg/dL). The effects of NPY on binge-like drinking are modulated by the Y1R and Y2R (but not Y5R) receptors. Importantly, our preliminary observations also revealed that binge-like drinking is associated with a significant reduction of NPY immunoreactivity in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Thus, the guiding hypothesis for the present proposal is that NPY signaling modulates binge- like alcohol intake. The proposed Aims will use powerful and innovative electrophysiological, histological (immunoreactivity), genetic (real-time PCR), and anatomical (site-directed manipulation of NPY signaling) techniques to determine if: A) binge-like alcohol drinking will be associated with altered NPY expression and receptor signaling that become rigid with repeated binge-like episodes (Aims 1 & 3), B) NPY receptor signaling within the extended amygdala modulates binge-like alcohol drinking (Aim 2), and C) the mechanism that triggers blunted NPY signaling and motivates binge-like drinking involves epigenetic elements, specifically alterations of histone acetylation (Aim 2). Expected results from the current project would identify Y1R agonists, Y2R antagonists, and compounds that increase histone acetylation as attractive targets for treating binge drinking. Pharmaceutical interventions useful for curbing and/or preventing binge drinking will not only help individuals avoid many of the dangerous health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.