Endocannabinoid Mechanisms in the Pathophysiology of Alcohol Use Disorders

酒精使用障碍病理生理学中的内源性大麻素机制

基本信息

批准号：
9402717
负责人：
Sachin Patel
金额：
$ 41万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9402717
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Abstinence Acute Affective Affective Symptoms Alcohol consumption Alcohol withdrawal syndrome Alcohols Amygdaloid structure Antidepressive Agents Anxiety Behavior Behavioral Biochemical Genetics Brain CNR1 gene Cell Nucleus Cells Characteristics Chronic Corticotropin-Releasing Hormone Cues Data Disease Electrophysiology (science)Elements Endocannabinoids Environment Feeling Functional disorder Generations Glutamates Human Hyperactive behavior Individual Insula of Reil Link Mediating Mental Depression Modeling Mood Disorders Moods Negative Reinforcements Neurons Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenotype Physiological Play Population Prevalence Process Recruitment Activity Regulation Relapse Rodent Role Selective Serotonin Reuptake Inhibitor Signal Transduction Specificity Structure of terminal stria nuclei of preoptic region Substance abuse problem Symptoms Synapses Synaptic plasticity System Testing Therapeutic Time adverse outcome affective disturbance alcohol abstinence alcohol seeking behavior alcohol use disorder associated symptom base depressive symptoms drinking driving force effective therapy endocannabinoid signaling in vivo insight mouse model negative affect neural circuit neuroimaging marker neuroregulation novel novel strategies optogenetics patch clamp prevent response withdrawal-induced anxiety

项目摘要

PROJECT SUMMARY Alcohol use disorders (AUDs) manifest from a convergence of characteristics of the individual, the environment, and the alcohol itself. The affective disturbances associated with alcohol withdrawal are examples of this convergence and represent a critical barrier to successful treatment. Reduction of these affective disturbances has been suggested to represent an important conceptual approach to reduce negative reinforcement-based alcohol intake in dependent individuals. However, treatment of these affective disturbances is complicated by data indicating reduced efficacy of antidepressants such as selective-serotonin reuptake inhibitors (SSRIs) in patients with AUDs, and that these traditional treatments can actually increase alcohol intake in some people;; thus, alternate non-monoamine-based treatment approaches for affective symptoms associated with AUDs are critically needed. Here we will test the novel hypothesis that pharmacological augmentation of endogenous cannabinoid signaling could represent an effective treatment for negative affective states associated with alcohol withdrawal including anxiety and depression, and could thereby facilitate abstinence in patients with AUDs. We will test the overall hypothesis that 2- arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling reduces anxiety and depressive-like behaviors associated with acute and protracted alcohol withdrawal in a mouse model of voluntary alcohol consumption. To interrogate the underlying mechanism of this effect, we will test the hypothesis that insula cortical-extended amygdala circuits are hyperactive during alcohol withdrawal and that over activation of this circuit is causally linked to the affective phenotypes observed during alcohol withdrawal. Finally, we will test the hypothesis that 2-AG-mediated inhibition of insula-extended amygdala circuit activity represents a key mechanism by which endocannabinoid signaling reduces alcohol withdrawal-induced anxiety and depressive- like behaviors. These data could provide new insight into the neural circuit mechanisms responsible for generating negative affective states associated with alcohol withdrawal, and reveal novel neuromodulatory mechanisms capable of counteracting these processes. If successful, these studies could support advancement of 2-AG-based pharmacological treatments for AUDs and co-morbid affective disorders.

项目摘要酒精使用障碍（AUD）表现出来自个人特征的收敛性，环境和酒精本身。与戒酒有关的情感障碍是这种收敛的例子，代表了成功治疗的关键障碍。减少这些有人建议情感障碍代表一种重要的概念方法来减少负面基于辅助的人摄入依赖的人。但是，对这些情感的处理扰动变得复杂，表明抗抑郁药（例如选择性 - 塞罗宁素）的有效性降低 AUD患者的再摄取抑制剂（SSRI），这些传统治疗方法实际上可以增加某些人的酒精摄入;因此，情感的替代性非单胺治疗方法与AUD相关的症状至关重要。在这里，我们将测试新的假设内源性大麻素信号传导的药理增强可以代表有效的治疗方法与戒酒有关的负面情感状态，包括焦虑和抑郁，可能从而有助于助听器患者的戒酒。我们将测试2- 蛛网膜（2-AG）介导的内源性大麻素信号传导可减少焦虑和抑郁样在自愿酒精的小鼠模型中与急性和受保护酒精戒断相关的行为消耗。为了审问这种效果的潜在机制，我们将检验以下假设。皮质延伸的杏仁核电路在戒酒期间过度活跃，并且过度激活电路在与Drawal的专辑中观察到的受影响的表型有关。最后，我们将测试假设2-AG介导的裂隙延伸杏仁核电路活性代表了一个关键内源性大麻素信号传导通过吸收诱发的焦虑和抑郁 - 喜欢行为。这些数据可以提供有关负责神经电路机制的新见解。产生与戒酒相关的负面情感状态，并揭示新的神经调节性能够抵消这些过程的机制。如果成功，这些研究可以支持基于2 AG的AUD和联合性情感障碍的药物治疗的进步。