Context and Relapse to Ethanol-Seeking

描述（由申请人提供）：与酒精相关的环境线索，如果在与过去饮酒相关的环境背景中经历，而不是在从未饮酒的环境中经历，则更有可能促成复发。在此，我们将研究复发行为模型中对酒精条件线索反应的情境调节，在该模型中，大鼠在独特的环境中接受训练，以区分一种与酒精配对的听觉刺激（CS+）和另一种从未与酒精配对的听觉刺激（CS-）；条件反应是通过在CS+过程中相对于CS-过程中进入酒精输送端口的数量增加来测量的。在不同情境下的反应消失后，回到原来的酒精训练环境会增强CS+驱动的酒精寻求行为（“复发”）。利用这种模式，我们建议利用特定部位的显微注射和体内电生理学技术，研究线索诱导的酒精寻找的神经回路。具体来说，我们假设对离散酒精预测线索的反应的恢复需要从基底外侧杏仁核（BLA）到伏隔核（NACc）的兴奋性投射，而酒精环境下这种行为的增强需要从腹侧海马（vHipp）到BLA的输出。在Aim 1中，我们将研究BLA和NACc的独立作用，以及BLA-NACc途径在线索诱导的酒精寻求中的作用。目的2将确定寻求酒精的情境控制是否通过vHipp对BLA的传入发生。目的3将通过检查神经元对BLA中酒精预测线索的反应，以及它们在环境中的调节，进一步定义所涉及的神经机制。总的来说，这些研究将完善我们对酒精寻求的环境调节的神经基础的理解，并可能产生新的治疗酒精中毒复发的治疗方法。

DESCRIPTION (provided by applicant): Environmental cues associated with alcohol are more likely to precipitate relapse if experienced in an environmental context associated with past alcohol consumption, as opposed to a context in which alcohol was never consumed. Here we will study contextual modulation of responding to alcohol-conditioned cues in behavioral models of relapse in which rats are trained in a distinctive context to discriminate between one auditory stimulus paired with alcohol (CS+) and a second (CS-) that is never paired with alcohol; conditioned responding is measured as increased entries into the alcohol delivery port during the CS+ relative to the CS-. After extinction of responding in a different context, placement back into the original alcohol training environment enhances CS+-driven alcohol-seeking behavior ('relapse'). Using this paradigm, we propose to investigate the neural circuitry underlying the modulation of cue-induced alcohol-seeking by context using techniques of site-specific microinjections and in vivo electrophysiology. Specifically, we hypothesize that reinstatement of responding to a discrete alcohol-predictive cue requires excitatory projections from the basolateral amygdala (BLA) to the nucleus accumbens core (NACc), whereas the augmentation of this behavior by an alcohol context requires efferents from the ventral hippocampus (vHipp) to the BLA. In Aim 1 we will examine the independent roles of the BLA and NACc, as well as the BLA-NACc pathway, in cue- induced alcohol-seeking. Aim 2 will determine if contextual control over alcohol-seeking occurs via vHipp efferents to the BLA. Aim 3 will further define the neural mechanisms involved by examining neuronal responses to alcohol-predictive cues in the BLA, their modulation by context. Collectively, these studies will refine our understanding of the neural underpinnings of contextual modulation of alcohol-seeking, and may give rise to new therapeutic treatments for relapse in alcoholism. PUBLIC HEALTH RELEVANCE: Exposure to stimuli that have been associated with past alcohol use is thought to contribute to propensity to relapse in human alcoholics. The environment in which alcohol was habitually consumed may be a particularly potent relapse cue. The studies in this proposal are designed to reveal neurobiological mechanisms that underlie the ability of alcohol-associated contexts to trigger relapse.