Synaptic Mechanisms underlying sex-differences in alcohol use disorder

酒精使用障碍（AUD）是一个主要的公共卫生问题。杏仁核中央核（CeA） 作为压力和焦虑处理的中心，在相关的负面影响中起着至关重要的作用。 酒精依赖和戒断/戒断。啮齿类动物研究属性消极， 与酒精依赖有关的强迫行为，与神经递质之间的“不平衡”有关。 大脑的促压力和抗压力系统。促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素（NE） 促应激系统在成瘾的行为方面是至关重要的，包括药物的致焦虑作用。 戒断我们已经描述了酒精和CRF作用的细胞机制， GABA和谷氨酸信号通路与酒精依赖诱导的雄性大鼠大脑中动脉神经适应 此外，我们发现NE，像CRF一样，强烈地调节CeA GABA能的传递， 依赖性和撤回的雄性大鼠，并确定了特定的肾上腺素能受体介导这些影响。 然而，尚不清楚雌性大鼠是否发生类似的功能变化。值得注意的是，我们的初步数据 确定了令人信服的性别特异性差异，表明CeA GABA能突触对 FQ（nociceptin）中酒精、CRF、NE和Nociceptin/Nociceptin的急性效应。关于后者， 阿片样肽孤啡肽通过抵消内源性CRF在神经元中的作用发挥抗应激作用。 我们的初步数据表明，痛敏肽也可能抵消NE的功能。令人惊讶的是， 研究了这些神经递质系统对CeA信号的影响，以性别依赖的方式。 利用这些最新的初步发现，本项目的主要目标是检验以下假设： 1)CeA回路中的促应激（CRF和NE）和抗应激（伤害感受素）系统的适应性变化是 差异和性别特异性招募或抑制通过酒精依赖，和2）中断 这些系统之间的平衡导致CeA活性的显著失调， 与酒精依赖和戒酒相关的负面影响，以及酒精的性别差异 虐待模式我们提出了两个具体的目标与多学科的方法，使用体外 电生理学，分子生物学和行为研究，以提供基本的机械数据， 阐明AUD对应激和复发易感性的细胞基础。更好地理解 神经适应塑造参与酒精依赖的突触网络是一个挑战， 酒精研究人员，将是至关重要的，以确定新的有前途的途径，为治疗目的， 缓解AUD。

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In addition, we found that NE, like CRF, strongly modulates CeA GABAergic transmission in naive, alcohol dependent, and withdrawn male rats, and identified specific adrenergic receptors that mediate these effects.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.