Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety

酒精使用障碍(AUD)影响着约1700万美国人，每年导致超过250万人死亡 仅在美国，每年就要花费美国2490亿美元。患有澳门氏症的人经常 戒断过程中的负性情绪(WD)与抑郁情绪、焦虑呈正相关 在禁欲期间复发。个体对酒精做出反应的神经生物学机制， 以及他/她患上AUD的倾向，还没有完全被理解。急、慢性酒精中毒 中脑皮质边缘回路的神经传递，包括腹侧被盖区(VTA)和慢性酒精 还改变了中央杏仁核(CEA)的神经传递，这是WD期间焦虑增加的一个区域。 VTA和CEA之间存在功能联系，尽管这些区域中的每一个都对 成瘾行为中，它们之间的联系在成瘾行为中的作用尚不清楚。我们的预赛 数据表明，酒精WD激活了酒精依赖动物的VTA-CEA回路。这款K01的目标是 建议确定这种电路激活的潜在机制，以及电路的贡献 导致WD期间焦虑样行为的增加。这一提议的首要假设是，CEA-投射 VTA多巴胺(DA)神经元在酒精WD时通过OX1R介导的激活 机制，而这个回路的激活在依赖相关增加的发展中是至关重要的 在急性WD期间出现焦虑样行为。为了验证这一假设，该提案将使用以下组合 解剖学、细胞学、成像、基于电路的和行为技术。这项建议将提供一个有希望的 通过实验获得重要研究培训和职业发展机会的年轻科学家 他们使用一种综合的方法来检验预测：(1)在体外观察到的VTA-CeADA活性增加 在慢性酒精引起的WD过程中，OX1R/内源性大麻素(ECB)信号介导，(2)CEA增加 在慢性酒精引起的WD期间观察到的活体活动是由VTA增加的DA输入介导的，并且 (3)VTA OX1R/ECB信号转导酒精WD诱导的焦虑样行为。这些研究的结果 研究将开辟神经科学研究的新途径，探索大脑奖励和 上瘾时的大脑压力系统。这项工作也可能为制定治疗策略提供信息，以减少 AUD患者的负性情感症状导致生活质量和健康的改善 受影响的个人，并减少与这些疾病相关的发病率。

Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $249 billion annually. Humans with AUD often experience negative affect during withdrawal (WD), and depressed mood and anxiety are positively correlated with relapse during abstinence. The neurobiological mechanisms underlying an individual’s response to alcohol, and his/her propensity to develop AUD, are not entirely understood. Acute and chronic alcohol alter neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and chronic alcohol also alters neurotransmission in the central amygdala (CeA), an area involved in increased anxiety during WD. There is a functional connection between the VTA and CeA, and although each of these regions is important for addictive behavior, the role of the connection between them in addictive behaviors is unknown. Our preliminary data indicate that alcohol WD activates the VTA-CeA circuit in alcohol-dependent animals. The goal of this K01 proposal is to determine the mechanism underlying this circuit activation, as well as the contribution of the circuit to increased anxiety-like behavior during WD. The overarching hypothesis of this proposal is that CeA-projecting VTA dopamine (DA) neurons become activated during alcohol WD via an orexin 1 receptor (OX1R)-mediated mechanism, and that activation of this circuit is critical in the development of dependence-associated increased anxiety-like behavior during acute WD. To test this hypothesis, the proposal will utilize a combination of anatomical, cellular, imaging, circuit-based and behavioral techniques. This proposal will provide a promising young scientist with vital research training and professional development opportunities facilitated by experiments that use an integrative approach to test the predictions that: (1) increased VTA-CeADA activity observed in vitro during WD from chronic alcohol is mediated by OX1R/endocannabinoid (eCB) signaling, (2) that increased CeA activity observed in vivo during WD from chronic alcohol is mediated by increased DA input from the VTA, and (3) that VTA OX1R/eCB signaling mediates alcohol WD-induced anxiety-like behavior. The results of these studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and brain stress systems in addiction. This work may also inform development of treatment strategies for reducing negative affective symptoms in individuals with AUD, leading to improvements in quality of life and health of affected individuals, and decreasing morbidity associated with these disorders.