Pharmacotherapy for Alcohol Dependence and Relapse

在美国，酗酒是一个严重的医疗和社会问题，复发是一个主要的 对治疗努力的挑战。目前，还没有完全令人满意的治疗干预措施。 预防复发和持续禁欲。虽然众所周知，依赖会导致 故态复萌，这个问题还没有得到彻底的研究。这项提案的重点和总体目标是 利用乙醇依赖和复发的小鼠模型评估药物治疗的能力 减少自愿饮用乙醇，以及可能成为动机的神经化学改变 与非依赖的动物相比，依赖的动物更容易喝酒。当代对酒精和毒品的看法 上瘾表明大脑内不同神经化学系统的激活(“动机”) 回路在建立乙醇的初始强化效应和形成过程中起着关键作用 在上瘾的后期阶段持续使用/滥用乙醇的动力。中边缘 以伏隔核为主要靶点的多巴胺通路是其重要组成部分。 这条线路的。在影响这条多巴胺途径的几个神经递质系统中， 谷氨酸的传递在乙醇的激励作用中起到了关键作用。一个 这一建议的指导原则是，激活中脑边缘多巴胺通路起着重要的作用 在建立乙醇的急性增强特性中的作用，同时多巴胺和 谷氨酸传递有助于促进复发并产生过量的乙醇 具有依赖特征的饮酒行为。这项研究计划需要使用体内微透析 核内细胞外多巴胺和谷氨酸水平变化的研究程序 与自愿饮用乙醇有关的伏立本，以及对各种药理作用的评价 有能力影响伴随行为(饮酒)和相关行为的药物 依赖和复发模型中的神经化学变化。该提案的总体目标是 提供有关酒精依赖型饮酒与非依赖型饮酒的神经基础的新信息 受试者，以及评估潜在药物治疗对两者的影响的能力 与依赖和复发有关的神经化学和行为(饮酒)变化。

Alcoholism is a substantial medical and social problem in the U.S. and relapse represents a major challenge to treatment efforts. Currently, there is no therapeutic intervention that is fully satisfactory in preventing relapse and sustaining abstinence. While dependence is known to contribute to the problem of relapse, this issue has not been thoroughly studied. The focus and overall objective of this proposal is to utilize a mouse model of EtOH dependence and relapse to evaluate the ability of pharmacotherapies to reduce voluntary EtOH drinking, as well as neurochemical alterations that may underlie motivation to drink in dependent compared to non-dependent animals. A contemporary view of alcohol and drug addiction indicates that activation of different neurochemical systems within the brain reward ("motive") circuitry play a critical role in establishing the initial reinforcing effects of EtOH, as well as shaping motivational forces that perpetuate EtOH use/abuse during later stages in addiction. The mesolimbic dopamine pathway, with the nucleus accumbens being a key target structure, is a prominent component of this circuitry. Among several neurotransmitter systems that impinge on this dopamine pathway, glutamate transmission has emerged as a key player in contributing to the motivational effects of EtOH. A guiding principle of this proposal is that activation of the mesolimbic dopamine pathway plays an important role in establishing the acute reinforcing properties of EtOH, while adaptive changes in dopamine and glutamate transmission contribute to conditions that promote relapse and engender excessive EtOH drinking behavior characteristic of dependence. The research plan entails use of in vivo microdialysis procedures to characterize changes in extracellular levels of dopamine and glutamate in nucleus accumbens associated with voluntary EtOH drinking, as well as evaluation of various pharmacological agents for their ability to influence concomitant measures of behavior (drinking) and associated neurochemical changes in the model of dependence and relapse. The overall goal of the proposal is to provide new information about neural substrates underlying EtOH drinking in dependent compared to nondependent subjects, as well as evaluate the ability of potential pharmacotherapeutics to impact both neurochemical and behavioral (drinking) changes related to dependence and relapse.