Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorders

描述(申请人提供)：酒精使用障碍的发展和进展被认为涉及神经回路的适应性变化，这些变化是负面情感状态(如焦虑)的基础。一个正在获得越来越多支持的假设是，这些适应性变化逐渐将酒精的动机从积极的强化(例如，欣快感)转移到消极的强化(例如，从消极的情感状态中解脱)。虽然关于酒精的积极强化作用的神经基础已知很多，但将消极强化与酒精中毒联系起来的神经底物仍不太清楚。外侧/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与焦虑障碍和成瘾的病理生理有关。令人惊讶的是，关于这一大脑区域的内在回路或影响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，我们发现β3-肾上腺素受体的激活增强了BLA中一个新的GABA回路，并且这种作用可以减少焦虑样行为和酒精寻找行为。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，我们证明了啮齿动物早期应激模型会产生几种行为和神经生物学变化，这些变化也与酒精中毒的易感性增加有关。这项提案的前两个目标将决定神经生物学 腺苷A1和A2a受体激活对大鼠杏仁基底外侧核(BLA)兴奋性和抑制性神经传递的影响，以及这些受体在BLA内的激活是否减少了焦虑样行为的测量。AIMS 3和4将使用早期生活应激模型来识别去甲肾上腺素和腺苷调节BLA突触传递的持久扰动，这些扰动可能有助于增加对过度饮酒行为的脆弱性(和弹性)。其他实验将确定，恢复正常血乳酸功能的药物操作是否可以减少因早期生活压力而导致的焦虑样行为和饮酒增加。

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.