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，每年导致超过 250 万人死亡 仅在美国，每年就花费 2,490 亿美元。经常携带 AUD 的人 戒断期间经历负面情绪（WD），抑郁情绪与焦虑呈正相关 禁欲期间复发。个体对酒精反应的神经生物学机制， 以及他/她发展澳元的倾向尚未完全了解。急性和慢性酒精改变 中皮质边缘回路的神经传递，包括腹侧被盖区 (VTA) 和慢性酒精 它还会改变中央杏仁核 (CeA) 的神经传递，该区域与 WD 期间的焦虑增加有关。 VTA 和 CeA 之间存在功能联系，尽管这些区域中的每一个对于 成瘾行为，但它们之间的联系在成瘾行为中的作用尚不清楚。我们的初步 数据表明，酒精 WD 会激活酒精依赖动物的 VTA-CeA 回路。本次K01的目标 建议是确定该电路激活的机制，以及电路的贡献 WD 期间焦虑样行为增加。该提案的总体假设是 CeA 投影 VTA 多巴胺 (DA) 神经元在酒精 WD 期间通过食欲素 1 受体 (OX1R) 介导被激活 机制，并且该电路的激活对于依赖性相关增加的发展至关重要 急性WD期间的焦虑样行为。为了检验这一假设，该提案将结合使用 解剖学、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) 体外观察到的 VTA-CeADA 活性增加 长期饮酒期间的 WD 是由 OX1R/内源性大麻素 (eCB) 信号传导介导的，(2) 增加了 CeA 长期饮酒期间在体内观察到的活动是由来自 VTA 的 DA 输入增加介导的，并且 (3) VTA OX1R/eCB 信号介导酒精 WD 诱导的焦虑样行为。这些结果 研究将为神经科学研究开辟新途径，探索大脑奖励与 成瘾中的大脑压力系统。这项工作还可能为制定治疗策略提供信息，以减少 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。