Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorders

酒精使用障碍的脆弱性和恢复力的突触相关性

• 批准号: 9056448
• 负责人: JEFFREY L WEINER
• 金额: $ 34.88万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056448
• 关键词: Acute; Adenosine; Adrenergic Receptor; Adult; Adverse effects; Affective; Agonist; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Experimentation; Anxiety; Anxiety Disorders; Attenuated; Behavioral; Brain region; Cells; Chronic; Development; Disease; Electrophysiology (science); Equilibrium; Etiology; Euphoria; Figs - dietary; Functional disorder; Funding; Glutamates; Goals; Health; Human body; Individual; Infusion procedures; Interneurons; Intervention; Knowledge; Lateral; Lead; Life Stress; Link; Measures; Mediating; Modeling; Motivation; Negative Reinforcements; Neural Pathways; Neurobiology; Neuromodulator; Norepinephrine; Pathway interactions; Pharmacological Treatment; Pharmacotherapy; Play; Positive Reinforcements; Publishing; Rattus; Receptor Activation; Regulation; Research Design; Rodent; Rodent Model; Role; Scanning; Signal Transduction; Synapses; Synaptic Transmission; System; Testing; addiction; alcohol exposure; alcohol seeking behavior; alcohol use disorder; alcoholism therapy; anxiety-like behavior; base; drinking behavior; effective therapy; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; neural circuit; neurobiological mechanism; neuroregulation; neurotransmission; novel; postsynaptic; receptor; relating to nervous system; research study; resilience

DESCRIPTION (provided by applicant): The development and progression of alcohol use disorders is thought to involve adaptive changes in neural circuits that underlie negative affective states, like anxiety. One hypothesis that is garnering increasing support is that these adaptive changes gradually shift motivation for alcohol away from positive reinforcement (e.g. euphoria) toward negative reinforcement (e.g. relief from negative affective states). Although much is known about the neural underpinning of alcohol's positive reinforcing effects, the neural substrates linking negative reinforcement and alcoholism remain less clearly defined. The lateral/basolateral amygdala (BLA) plays a major role in anxiety-like behaviors and alcohol drinking and there is growing evidence that dysregulation of this brain region contributes to the pathophysiology of both anxiety disorders and addiction. Surprisingly, much remains unknown about the intrinsic circuitry of this brain region or the neuromodulatory systems that influence BLA synaptic transmission. During the last funding period, we discovered that beta3-adrenoceptor activation enhances a novel GABA circuit in the BLA and that this effect can decrease anxiety-like behaviors and ethanol seeking behaviors. We have also recently identified powerful effects of the neuromodulator adenosine on BLA synaptic transmission. In other studies, we demonstrated that a rodent early life stress model engenders several behavioral and neurobiological alterations that have also been associated with increased vulnerability to alcoholism. The first two aims of this proposal will determine the neurobiological effects of adenosine A1 and A2a receptor activation on excitatory and inhibitory neurotransmission in the rat basolateral amygdala (BLA) and whether intra-BLA activation of these receptors reduces measures of anxiety-like behavior. Aims 3 and 4 will employ the early life stress model to identify enduring perturbations in norepinephrine and adenosine modulation of BLA synaptic transmission that may contribute to increased vulnerability (and resilience) to excessive alcohol drinking behaviors. Other experiments will determine if pharmacological manipulations that restore normal BLA function can reduce the increases in anxiety-like behavior and ethanol drinking that result from early life stress.

描述（由申请人提供）：酒精使用障碍的发展和进展被认为与神经回路的适应性变化有关，这种变化是消极情感状态（如焦虑）的基础。有一种假说得到了越来越多的支持，即这些适应性变化逐渐将饮酒动机从积极强化（如快感）转向消极强化（如从消极情感状态中解脱出来）。尽管我们对酒精的积极强化效应的神经基础已经了解很多，但将消极强化和酗酒联系起来的神经基础仍然不太清楚。侧/基底外侧杏仁核（BLA）在焦虑样行为和饮酒中起着重要作用，越来越多的证据表明，这一大脑区域的失调有助于焦虑症和成瘾的病理生理。令人惊讶的是，关于这一大脑区域的内在电路或影响BLA突触传递的神经调节系统，仍有许多未知之处。在上一个资助期间，我们发现β -肾上腺素受体激活增强了BLA中一个新的GABA回路，这种效应可以减少焦虑样行为和酒精寻求行为。我们最近也发现了神经调节剂腺苷对BLA突触传递的强大影响。在其他研究中，我们证明了啮齿动物的早期生活压力模型会产生一些行为和神经生物学上的改变，这些改变也与酗酒的易感性增加有关。该提案的前两个目标将决定神经生物学