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

基本信息

批准号：
10604321
负责人：
MARISA ROBERTO
金额：
$ 40.73万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
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/10604321
关键词：
Abstinence Accounting Acute Adrenergic Receptor Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Intoxication Alcoholism 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 Psychological reinforcement Public Health Rattus Regulation Relapse Research Research Personnel Rodent Role Sex Differences Shapes Signal Transduction Stress Synapses System Testing Therapeutic Transgenic Organisms Withdrawal Withdrawal Symptom 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

项目摘要

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）是一个主要的公共卫生问题。杏仁核的中央核（CEA）充当压力和焦虑处理的枢纽，并且在相关的负面影响中起着至关重要的作用与酒精依赖和戒酒/戒断有关。啮齿动物研究归因于负面，加固驱动的与酒精依赖对神经递质之间“不平衡”相关的强迫行为大脑亲应力和抗压力系统。皮质激素释放因子（CRF）和去甲肾上腺素（NE）均两者亲压力系统在成瘾的行为方面至关重要，包括药物的焦虑作用提取。我们已经表征了酒精和CRF作用涉及的细胞机制 GABA和谷氨酸信号传导以及雄性大鼠CEA诱导的神经适应性。此外，我们发现NE像CRF一样强烈调节幼稚的酒精中的CEA GABA能传播依赖和退出雄性大鼠，并确定了介导这些作用的特定肾上腺素受体。但是，尚不清楚女性大鼠是否发生了类似的功能改变。值得注意的是，我们的初步数据确定了引人注目的性别差异，表明CEA GABA能突触的敏感性有所不同酒精，CRF，NE和Nocteptin/Orphanin FQ（NociTeptin）的急性影响。关于后者，阿片样肽肽症症状通过抵消内源性CRF的功能发挥抗压力作用大脑和我们的初步数据表明，诺耐匹毒素也可能抵消NE功能。令人惊讶的是，没有研究已经检查了这些神经递质系统对CEA信号的影响。利用这些最近的初步发现，该项目的主要目的是检验以下假设。 1）CEA电路中的亲应力（CRF和NE）和抗压力（Nociceptin）系统的自适应变化是通过酒精依赖性差异和性别特定招募或抑制，2）这些系统之间的平衡导致CEA活性的明显失调，这有助于与酒精依赖和戒酒有关的负面影响以及酒精的性别差异滥用模式。我们提出了使用体外的多学科方法提出的两个特定目标电生理学，分子生物学和行为研究，以提供基本的机械数据阐明AUD对压力和缓解的敏感性的细胞基础。更好地理解塑造与酒精依赖相关的突触网络的神经适应性代表了对酒精研究人员将对确定治疗目的的新承诺至关重要减轻音调。