Neuropeptide Y: Role in Ethanol Intake and Sensitivity

描述（由申请人提供）：戒酒者的酒精中毒和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方法。然而，非依赖性个体的大量饮酒和酗酒却很少受到关注。美国国家酒精滥用和酒精中毒研究所（NIAAA）将“狂欢”定义为在短时间内血液酒精浓度（BACs）超过0.08%（80毫克/分升）的一种饮酒模式。频繁的酗酒与许多负面后果有关，包括患情绪障碍、高血压、心脏病和2型糖尿病的可能性增加。最令人担忧的是，经常狂饮会大大增加人们产生酒精依赖的风险。因此，确定大脑中调节酗酒的神经化学途径至关重要，因为这些知识将为新的药物治疗提供见解，以防止这种危险行为。神经肽Y （NPY）在涉及酒精神经生物学反应的大脑区域中表达，NPY可以防止过量酒精摄入相关的依赖。因此，我们最近研究了NPY受体信号在暴饮暴食中的作用。中央给药NPY显著减弱了狂饮样饮酒（在没有NPY的情况下，BACs达到100 mg/dL的小鼠），但没有减少中等水平消费小鼠的饮酒（与BACs <25 mg/dL相关）。NPY对狂饮的影响是由Y1R和Y2R（但不是Y5R）受体调节的。重要的是，我们的初步观察还显示，狂饮样饮酒与杏仁核中央核（CeA）和终纹床核（BNST）的NPY免疫反应性显著降低有关。因此，本建议的指导假设是NPY信号调节暴饮暴食样酒精摄入。拟议的Aims将使用强大和创新的电生理、组织学（免疫反应性）、遗传学（实时PCR）和解剖学（NPY信号的定点操作）技术来确定：A)暴饮暴食将与NPY表达和受体信号的改变有关，这种改变会随着反复的暴饮暴食而变得刚性（目的1和3）；B)扩展杏仁核内的NPY受体信号调节暴饮暴食（目的2）；C)触发NPY信号钝化并激发暴饮暴食的机制涉及表观遗传因素，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Y1R激动剂、Y2R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。抑制和/或预防酗酒的药物干预不仅可以帮助个人避免与经常酗酒有关的许多危险的健康后果，而且可以保护脆弱的个人不发展到酒精依赖的地步。

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. PUBLIC HEALTH RELEVANCE: While current research is underway to identify potential pharmaceutical treatments for preventing excessive alcohol intake associated with dependence, far less attention is given to potential treatments to curb excessive binge drinking in non-dependent individuals, despite numerous negative health consequences associated with this dangerous behavior. Research has established that compounds aimed at neuropeptide Y (NPY) receptors are protective against dependence-induced alcohol drinking, and our preliminary findings suggest that compounds targeting NPY receptors are also protective against excessive binge-like drinking in mice. Expected results will verify that compounds aimed at NPY receptors are useful for curbing and/or preventing binge drinking, and will not only help individuals avoid many of the health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.