Role of hypothalamic-specific POMC deficiency in alcohol reward and drinking

 描述(由申请人提供)：奥匹达能机制，特别是通过β-内啡肽参与奖赏和药物成瘾。在不同的酒精摄入啮齿动物模型中，阿片受体拮抗剂减少了酒精摄入量和复发性饮酒。β-内啡肽由前阿片黑素皮质素(POMC)基因编码。最近，我们利用撒丁岛嗜酒大鼠和C57BL/6J发现，自愿饮酒2周会增加大鼠和小鼠下丘脑POMC基因的表达。我们的假设是，下丘脑POMC基因表达的改变在酒精诱导的奖赏和酒精饮酒行为、依赖和复发的发展中起关键作用。在转基因小鼠中，POMC NPE(下丘脑特异性POMC增强子)的缺失选择性地取消了POMC在下丘脑中的表达，但在正常的垂体POMC细胞中。我们的第一个目标(特定目标1)是利用黑暗饮酒(DID)、慢性升级饮酒(CED)和条件性位置偏爱(CPP)模型，确定下丘脑POMC神经元在调节酒精奖赏和饮酒行为中的作用。POMC NPE缺失对酒精行为抑制的假说将为下丘脑POMC神经元参与酒精奖赏或复发性饮酒提供实验证据，而小鼠和人之间保守的POMC NPE增强子可能为发现控制POMC表达的转录因子进而饮酒提供有价值的平台。新的治疗药物可能会以这些转录因子为靶点，类似于目前对癌症和帕金森氏症的研究。我们的第二个目标(特定目标2)是同时分析酒精饮酒期间下丘脑POMC的表达谱，这表征了潜在的机制。我们将确定在饮用DID或CED或CPP后，下丘脑是否会发生区域特异性POMC变化。这项研究可能揭示潜在的新的分子机制，为理解酒精相关疾病的分子基础提供新的见解，并为酒精中毒的干预提供新的靶点。

 DESCRIPTION (provided by applicant): Opioidergic mechanisms particularly through beta-endorphin are involved in reward and drug addiction. In different rodent models of alcohol intake, opioid receptor antagonists decrease alcohol consumption and relapse-like drinking. Beta-endorphin is encoded by pro-opiomelanocortin (POMC) gene. Using Sardinian alcohol-preferring rats and C57BL/6J, we recently found that voluntary alcohol drinking for 2 weeks increases POMC gene expression in the hypothalamus of both rats and mice. Our hypothesis is that alterations of hypothalamic POMC gene expression are critical to alcohol-induced reward and the development of alcohol drinking behaviors, dependence and relapse. In transgenic mice, deletion of POMC nPEs (hypothalamic- specific POMC enhancers) abolishes POMC expression selectively in the hypothalamus, but with normal pituitary POMC cells. Our first goal (Specific Aim 1) is to determine the roles of hypothalamic POMC neurons in regulating alcohol reward and drinking behaviors in male and female nPE knockout mice, using drinking-in-the- dark (DID), chronic escalation drinking (CED) and conditioned place preference (CPP) models. The hypothesized reduction by POMC nPE deletion of alcohol behaviors would provide the experimental evidence that hypothalamic POMC neurons are involved in alcohol rewarding or relapse-like drinking, and the conserved POMC nPE enhancers between mice and men could provide a valuable platform for the discovery of transcription factors controlling the POMC expression, and then alcohol drinking. New therapeutic agents may target these transcription factors similarly to what is currently studied for cancer and Parkinson's disease. Our second goal (Specific Aim 2) is in parallel to analyze the hypothalamic POMC expression profiles during alcohol drinking that characterize an underlying mechanism. We will determine if region-specific POMC changes occur in the hypothalamus after DID or CED drinking, or CPP. The study may reveal potentially new molecular mechanisms that provide new insights for understanding the molecular basis of alcohol-related disorders and novel targets for intervention in alcoholism.