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

酒精使用障碍（AUD）影响约1700万美国人，每年造成250多万人死亡 仅在美国，每年就花费美国2490亿美元。AUD患者经常 在戒断过程中经历负性情感（WD），抑郁情绪与焦虑呈正相关 在禁欲期间复发个体对酒精反应的神经生物学机制， 以及他/她发展AUD的倾向，还不完全了解。急性和慢性酒精改变 包括腹侧被盖区（VTA）在内的中皮质边缘回路的神经传递与慢性酒精 也改变中央杏仁核（CeA）的神经传递，这是WD期间焦虑增加的一个区域。 VTA和CeA之间存在功能性联系，尽管这些区域中的每一个对于 成瘾行为，它们之间的联系在成瘾行为中的作用是未知的。我们的初步 数据表明酒精WD激活酒精依赖动物中的VTA-CeA回路。K 01的目标 一个建议是确定该电路激活的机制，以及电路的贡献 在WD期间增加焦虑样行为。这项建议的首要假设是， 在酒精性WD期间，腹侧被盖区多巴胺（DA）神经元通过食欲素1受体（OX 1 R）介导的 机制，并且该回路的激活在依赖性相关增加的发展中至关重要。 急性WD期间的焦虑样行为。为了检验这一假设，该提案将利用以下组合： 解剖、细胞、成像、基于电路和行为的技术。该提案将提供一个有希望的 年轻科学家通过实验获得重要的研究培训和专业发展机会 使用综合方法来测试以下预测：（1）体外观察到VTA-CeADA活性增加 在慢性酒精引起的WD期间，由OX 1 R/内源性大麻素（eCB）信号传导介导，（2）增加CeA 在慢性酒精引起的WD期间在体内观察到的活性由VTA增加的DA输入介导，并且 (3)VTA OX 1 R/eCB信号传导介导酒精WD诱导的焦虑样行为。的结果予以 这些研究将为神经科学研究开辟新的途径，探索大脑奖赏和大脑兴奋之间的相互作用。 大脑压力系统这项工作也可以为减少癌症的治疗策略的制定提供信息。 AUD患者的负面情感症状，导致生活质量和健康的改善， 受影响的个体，并降低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.