Neuropeptide Y: Role in Ethanol Intake and Sensitivity

描述(由申请人提供)：戒酒和戒酒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，非依赖型个人的酗酒和酗酒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“酗酒”定义为在短时间内血液酒精浓度(BAC)超过0.08%(80毫克/分升)的饮酒模式。频繁的酗酒与许多负面后果有关，包括增加患上情绪障碍、高血压和心脏病以及2型糖尿病的可能性。最令人担忧的是，经常酗酒会显著增加人们患上酒精依赖的风险。因此，确定大脑中调节酗酒的神经化学路径至关重要，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洞察。神经肽Y(NPY)在与酒精的神经生物学反应有关的脑区表达，NPY可以保护与依赖相关的过量酒精摄入。因此，我们最近研究了NPY受体信号在暴饮式饮酒中的作用。中枢注射NPY可显著抑制酗酒(在没有NPY的情况下BAC为100 mg/dL的小鼠)，但不能减少中等饮酒量的小鼠(BAC为25 mg/dL)的饮酒。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，酗酒与杏仁中央核(CEA)和终纹床核(BNST)的NPY免疫反应显著降低有关。因此，目前的建议的指导性假设是NPY信号调节类似狂欢的酒精摄入。拟议的目标将使用强大和创新的电生理学、组织学(免疫反应性)、遗传学(实时聚合酶链式反应)和解剖学(NPY信号的定点操纵)技术来确定：A)酗酒是否会与NPY表达和受体信号的变化有关(目标1和3)，B)杏仁核扩大的NPY受体信号调节酗酒(目标2)，以及C)触发钝化的NPY信号和激励狂饮的机制涉及表观遗传元件，特别是组蛋白乙酰化的变化(目标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。有助于遏制和/或防止酗酒的药物干预措施不仅将帮助个人避免与经常酗酒有关的许多危险的健康后果，还可能保护脆弱的个人不至于发展到酒精依赖的地步。 与公共健康相关：尽管目前正在进行研究，以确定防止与依赖相关的过度饮酒的潜在药物治疗方法，但对遏制非依赖个人过度饮酒的潜在治疗方法的关注要少得多，尽管这种危险行为会带来许多负面健康后果。研究证实，针对神经肽Y(NPY)受体的化合物对依赖诱导的酒精饮酒具有保护作用，我们的初步发现表明，针对NPY受体的化合物也对小鼠过度酗酒具有保护作用。预期的结果将证实，针对NPY受体的化合物有助于遏制和/或防止酗酒，不仅将帮助个人避免与经常酗酒相关的许多健康后果，还可能保护脆弱的个人，使其不至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. 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.