Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorders

描述（由申请人提供）：酒精使用障碍的发生和进展被认为涉及神经回路的适应性变化，而神经回路是负面情感状态（如焦虑）的基础。越来越多的支持的一个假设是，这些适应性变化逐渐将饮酒的动机从积极强化（例如欣快感）转向消极强化（例如从消极情感状态中缓解）。尽管人们对酒精的正强化作用的神经基础了解很多，但将负强化和酗酒联系起来的神经基础仍然不太明确。外侧/基底外侧杏仁核（BLA）在焦虑样行为和饮酒中发挥着重要作用，越来越多的证据表明，该大脑区域的失调会导致焦虑症和成瘾的病理生理学。 令人惊讶的是，关于该大脑区域的内在电路或影响 BLA 突触传递的神经调节系统，仍有很多未知之处。 在上一个资助期间，我们发现 β3-肾上腺素受体激活增强了 BLA 中的新型 GABA 回路，并且这种效应可以减少焦虑样行为和乙醇寻求行为。 我们最近还发现了神经调节剂腺苷对 BLA 突触传递的强大作用。在其他研究中，我们证明啮齿动物早期生活压力模型会引起一些行为和神经生物学改变，这些改变也与酗酒的脆弱性增加有关。该提案的前两个目标将决定神经生物学 腺苷 A1 和 A2a 受体激活对大鼠基底外侧杏仁核 (BLA) 兴奋性和抑制性神经传递的影响，以及 BLA 内这些受体的激活是否会减少焦虑样行为的测量。 目标 3 和 4 将采用早期生活压力模型来识别 BLA 突触传递的去甲肾上腺素和腺苷调节的持久扰动，这可能导致过度饮酒行为的脆弱性（和恢复力）增加。 其他实验将确定恢复正常 BLA 功能的药理学操作是否可以减少因早期生活压力导致的焦虑样行为和乙醇饮酒的增加。

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.