Pharmacotherapy for Alcohol Dependence and Relapse

酗酒在美国是一个严重的医学和社会问题，复发是一个主要的 对治疗工作的挑战。目前，没有治疗干预是完全令人满意的， 预防复发和维持禁欲。虽然依赖性是众所周知的， 复发，这个问题还没有得到彻底的研究。本建议的重点和总体目标是 利用EtOH依赖和复发的小鼠模型来评估药物治疗的能力， 减少自愿EtOH饮酒，以及神经化学变化，可能是动机的基础， 与不依赖的动物相比，依赖的动物更容易喝酒。当代对酒精和毒品的看法 成瘾表明，大脑中不同神经化学系统的激活奖励（“动机”） 电路在建立EtOH的初始增强效果以及形成 在成瘾后期使EtOH使用/滥用永久化的动机力量。中脑边缘 多巴胺通路是一个重要的组成部分，其中丘脑核是一个关键的靶结构， 这个电路。在影响多巴胺通路的几种神经递质系统中， 谷氨酸传输已经成为促成EtOH的激励作用的关键因素。一 该建议的指导原则是中脑边缘多巴胺通路的激活在脑内多巴胺的释放中起重要作用。 在建立EtOH的急性强化特性中的作用，而多巴胺和 谷氨酸传输有助于促进复发和产生过量EtOH的条件 依赖性的饮酒行为。该研究计划需要使用体内微透析 表征细胞核中多巴胺和谷氨酸的细胞外水平变化的方法 与自愿EtOH饮酒相关的药物，以及各种药理学评价 代理人的能力，影响伴随措施的行为（饮酒）和相关 依赖和复发模型中的神经化学变化。该提案的总体目标是 提供了新的信息，神经基板的基础乙醇饮用依赖相比，非依赖 受试者，以及评价潜在药物治疗对受试者的影响 与依赖和复发相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.