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

食欲素调节酒精戒断焦虑中大脑奖赏-大脑应激系统相互作用

• 批准号: 10302090
• 负责人: Elizabeth Minor Avegno
• 金额: $ 16.36万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302090
• 关键词: Abstinence; Acute; Addictive Behavior; Address; Adult; Affect; Affective Symptoms; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Amygdaloid structure; Anatomy; Animals; Anxiety; Area; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Calcium Signaling; Cannabinoids; Cessation of life; Chronic; Data; Dependence; Depressed mood; Development; Disease; Disinhibition; Dopamine; Electrophysiology (science); Endocannabinoids; Ethanol; Female; Fiber; Gene Expression; Goals; Health; Human; Image; In Vitro; Individual; Inhalation; Investigation; Mediating; Molecular Biology; Morbidity - disease rate; Mus; Neurobiology; Neurons; Neuropeptides; Neurosciences; Pharmacology; Photometry; Physiology; Quality of life; Rattus; Receptor Activation; Relapse; Research; Research Training; Rewards; Role; Scientist; Slice; Stress; System; Techniques; Testing; Training; United States; Ventral Tegmental Area; Viral; Withdrawal; Work; addiction; alcohol effect; alcohol research; alcohol response; alcohol use disorder; anxiety-like behavior; base; career; cost; dopaminergic neuron; endocannabinoid signaling; experience; experimental study; hypocretin; improved; in vivo; individual response; knock-down; male; negative affect; neuroadaptation; neurobiological mechanism; neurotransmission; orexin 1 receptor; orexin A; presynaptic; receptor expression; recruit; relating to nervous system; reward circuitry; skills; therapeutically effective; therapy development; treatment strategy; vapor; withdrawal-induced anxiety

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.

酒精使用障碍（AUD）影响约1700万美国人，每年造成超过250万人死亡 仅在美国，每年耗资2490亿美元。经常与aud的人 撤回期间（WD）的经历负面影响，情绪低落和动画呈正相关 节制期间松了一口气。个人对酒精反应的基础的神经生物学机制， 而且他/她的诺言承诺并不完全理解。急性和慢性酒精改变 中皮质骨纤维电路中的神经传递，包括腹侧对段区域（VTA）和慢性酒精 还改变了中央杏仁核（CEA）的神经传递，该区域涉及WD期间焦虑症的增加。 VTA和CEA之间存在功能连接，尽管这些区域中的每个区域都很重要 加性行为，它们之间的连接在加性行为中的作用是未知的。我们的初步 数据表明酒精WD激活酒精依赖性动物的VTA-CEA电路。这个K01的目标 建议是确定该电路激活的基础机制以及电路的贡献 在WD期间增加焦虑症行为。该提议的总体假设是CEA销售 VTA多巴胺（DA）神经元在酒精WD期间通过Orexin 1受体（OX1R）介导的 机制，该电路的激活对于依赖关系相关的发展至关重要 急性WD期间的焦虑行为。为了检验这一假设，该提案将利用 解剖学，细胞，成像，基于电路和行为技术。该提议将提供诺言 通过实验准备的重要研究培训和专业发展机会的年轻科学家 使用一种集成方法来测试以下预测：（1）在体外观察到的VTA-CEADA活性增加 在慢性酒精的WD期间，由OX1R/内源性大麻素（ECB）信号传导介导，（2）增加了CEA 慢性酒精期间在WD期间在体内观察到的活性是由VTA的DA输入增加而介导的，并且 （3）VTA OX1R/ECB信号传导介导了酒精WD诱导的类似动画的行为。这些结果 研究将开放神经科学投资的新途径，以探讨大脑奖励与 成瘾中的大脑压力系统。这项工作还可能为减少治疗策略的制定提供信息 AUD的个体负面情感症状，从而改善了生活质量和健康状况 受影响的个体，并降低了与这些疾病相关的发病率。