Synaptic Mechanisms underlying sex-differences in alcohol use disorder

酒精使用障碍性别差异背后的突触机制

• 批准号: 10378413
• 负责人: MARISA ROBERTO
• 金额: $ 39.94万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-10 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378413
• 关键词: Abstinence; Accounting; Acute; Adrenergic Receptor; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain; Cell Nucleus; Chronic; Complex; Compulsive Behavior; Corticotropin-Releasing Hormone; Cre driver; Data; Development; Disease; Electrophysiology (science); Elements; Equilibrium; Ethanol; Ethanol dependence; Female; Immunohistochemistry; Immunology procedure; In Situ Hybridization; In Vitro; Individual Differences; Intake; Laboratories; Lead; Mediating; Molecular; Molecular Biology; Negative Reinforcements; Neurons; Neurophysiology - biologic function; Neurotransmitters; Norepinephrine; Opioid; Pathway interactions; Pattern; Peptides; Play; Population; Predisposition; Public Health; Rattus; Regulation; Relapse; Research; Research Personnel; Rodent; Role; Sex Differences; Shapes; Signal Transduction; Stress; Synapses; System; Testing; Therapeutic; Transgenic Organisms; Withdrawal; addiction; alcohol abstinence; alcohol abuse therapy; alcohol availability; alcohol effect; alcohol use disorder; anxiety-like behavior; behavioral study; beta-adrenergic receptor; compulsion; design; drug withdrawal; dysphoria; gamma-Aminobutyric Acid; glutamatergic signaling; insight; interdisciplinary approach; locus ceruleus structure; male; negative affect; negative emotional state; neuroadaptation; nociceptin; norepinephrine system; novel; preclinical study; prevent; receptor; recruit; sex; sexual dimorphism; tool; transmission process; treatment strategy; withdrawal-induced anxiety

Alcohol use disorder (AUD) is a major public health problem. The central nucleus of the amygdala (CeA) functions as a hub of stress and anxiety processing and plays a crucial role in the negative affect associated with alcohol dependence and abstinence/withdrawal. Rodent studies attribute negative, reinforcement–driven compulsive behaviors associated with alcohol dependence to an “imbalance” between neurotransmitters in the brain pro-stress and anti-stress systems. Both corticotropin-releasing factor (CRF) and norepinephrine (NE) pro-stress systems are critical in behavioral aspects of addiction, including the anxiogenic effects of drug withdrawal. We have characterized the cellular mechanisms involved in the actions of alcohol and CRF on GABA and glutamate signaling, and the neuroadaptations induced by alcohol dependence in CeA of male rats. In addition, we found that NE, like CRF, strongly modulates CeA GABAergic transmission in naive, alcohol dependent, and withdrawn male rats, and identified specific adrenergic receptors that mediate these effects. However, it is unknown whether similar functional alterations occur in female rats. Notably, our preliminary data identified compelling sex-specific differences showing that CeA GABAergic synapses differ in their sensitivity to the acute effects of alcohol, CRF, NE and nociceptin/orphanin FQ (nociceptin). Concerning the latter, the opioid-like peptide nociceptin exerts anti-stress effects by counteracting the function of endogenous CRF in the brain, and our preliminary data show that nociceptin may also counteract NE functions. Surprisingly, no studies have examined the effects of these neurotransmitter systems on CeA signaling in a sex-dependent manner. Capitalizing on these recent preliminary findings, the main objective of this project is to test the hypothesis that 1) adaptive changes in pro-stress (CRF and NE) and anti-stress (nociceptin) systems in the CeA circuits are differentially and sex-specifically recruited or suppressed through alcohol dependence, and 2) the disrupted balance between these systems leads to significant dysregulation of CeA activity that contributes to the negative affect associated with alcohol dependence and abstinence, as well as the sex differences in alcohol abuse patterns. We propose two specific aims with a multidisciplinary approach using in vitro electrophysiology, molecular biology, and behavioral studies to provide essential mechanistic data that can elucidate the cellular basis of the susceptibility of AUD to stress and relapse. A better understanding of the neuroadaptations shaping the synaptic networks involved in alcohol dependence represents a challenge to alcohol researchers and will be critical toward identifying new promising avenues for therapeutic purposes to alleviate AUD.

酒精使用障碍(AUD)是一个主要的公共健康问题。杏仁中央核(CEA) 作为压力和焦虑处理的枢纽，在相关的负面情绪中起着至关重要的作用 有酒精依赖和禁欲/戒断。啮齿动物研究的属性是负面的，强化驱动的 与酒精依赖相关的强迫行为与大脑中神经递质之间的“失衡”有关 大脑支持应激和抗应激系统。促肾上腺皮质激素释放因子和去甲肾上腺素 前应激系统在成瘾的行为方面是至关重要的，包括药物的焦虑效应。 戒烟。我们已经确定了酒精和促肾上腺皮质激素释放因子作用于 GABA和谷氨酸信号转导与酒精依赖诱导的雄性大鼠CEA的神经适应。 此外，我们还发现，与CRF一样，NE对幼稚酒精中CEA-GABA能传递也有很强的调节作用 依赖和戒断雄性大鼠，并确定了介导这些效应的特定肾上腺素能受体。 然而，目前尚不清楚雌性大鼠是否也会发生类似的功能变化。值得注意的是，我们的初步数据 发现了显著的性别差异，表明CEA、GABA能突触对 酒精、CRF、NE和伤害素/孤儿FQ(伤害素)的急性影响。关于后者， 阿片肽Niceptin通过拮抗内源性CRF的作用发挥抗应激作用 我们的初步数据显示，伤害素也可能抵消NE的功能。令人惊讶的是，没有研究 以性别依赖的方式研究了这些神经递质系统对CEA信号的影响。 利用这些最新的初步发现，该项目的主要目标是检验以下假设 1)CEA回路中促应激(CRF和NE)和抗应激(伤害素)系统的适应性变化 通过酒精依赖而被招募或被抑制，以及2)被扰乱的人 这些系统之间的平衡导致CEA活动的严重失调，从而导致 与酒精依赖和戒酒有关的负面情绪，以及酒精中的性别差异 虐待模式。我们用体外多学科方法提出了两个特定的目标。 电生理学、分子生物学和行为研究，提供基本的机械数据，可以 阐明AUD对应激和复发易感性的细胞学基础。更好地理解 塑造涉及酒精依赖的突触网络的神经适应是对 酒精研究人员，并将在寻找治疗目的新的有希望的途径方面至关重要 缓解澳元。