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

 描述（由申请人提供）：阿片能机制，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消耗和复发性饮酒。β-内啡肽由前阿黑皮素（POMC）基因编码。使用撒丁岛的酒精偏好大鼠和C57 BL/6 J，我们最近发现，自愿饮酒2周增加POMC基因在大鼠和小鼠下丘脑的表达。我们的假设是，下丘脑POMC基因表达的改变对于酒精诱导的奖励以及饮酒行为、依赖和复发的发展至关重要。在转基因小鼠中，POMC nPE（下丘脑特异性POMC增强子）的缺失选择性地消除了下丘脑中的POMC表达，但具有正常的垂体POMC细胞。我们的第一个目标（具体目标1）是确定下丘脑POMC神经元在调节雄性和雌性nPE敲除小鼠的酒精奖励和饮酒行为中的作用，使用黑暗中饮酒（DID）、慢性递增饮酒（CED）和条件性位置偏好（CPP）模型。推测POMC nPE缺失可减少饮酒行为，为下丘脑POMC神经元参与酒精奖赏或复发样饮酒提供了实验证据，而小鼠和人之间保守的POMC nPE增强子可为发现控制POMC表达的转录因子，进而控制饮酒提供有价值的平台。新的治疗药物可能以这些转录因子为目标，类似于目前研究的癌症和帕金森病。我们的第二个目标（具体目标2）是在平行分析下丘脑POMC表达谱在饮酒过程中，表征一个潜在的机制。我们将确定DID或CED饮酒或CPP后下丘脑是否发生区域特异性POMC变化。这项研究可能揭示潜在的新分子机制，为理解酒精相关疾病的分子基础和干预酒精中毒的新靶点提供新的见解。

 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.