RC1 PHARMACOTHERAPY AND MECHANISMS OF ETHANOL DEPENDENCE AND RELAPSE DRINKING

酗酒是一种慢性复发的疾病，在美国仍然是一个严重的医疗和社会问题，需要加强努力来治疗它。我们对饮酒动机的潜在机制，特别是从适度饮酒过渡到过度和不受控制饮酒的机制的理解的进展，是开发新的和更有效的治疗策略的关键。当代关于酒精成瘾的观点认为，纹状体区域内谷氨酸（GLU）和多巴胺（DA）传递的适应性（纹状体是神经回路中介导动机行为的关键成分）在调节乙醇饮酒行为中起着重要作用。虽然我们目前的研究主要集中在腹侧纹状体（即伏隔核；NAc）的神经化学适应上，但最近的证据表明，背外侧纹状体（DLS）中GLU和DA传递的适应可能在调节从控制饮酒到不受控制的强迫饮酒的转变中发挥了重要作用，这是乙醇依赖的特征。因此，本提案的总体目标是检查GLU和DA在背侧纹状体中的传输适应性，这可能在质量或数量上与腹侧纹状体不同，并评估药物治疗对自主酒精饮用的影响，以及依赖动物与非依赖动物之间可能构成饮酒动机的神经化学改变。该建议的指导原则是乙醇依赖与GLU和DA在背外侧纹状体内的传递适应性有关，并在驱动从适度控制饮酒到不受控制的过度饮酒的转变中起着不可或缺的作用。研究

Alcoholism is a chronic relapsing disorder that continues to be a serious medical and social problem in the U.S. and enhanced efforts are needed to treat it. Advances in our understanding about mechanisms underlying motivation to drink and, in particular, mechanisms that drive transition from moderate drinking to more excessive and uncontrolled drinking are key to developing new and more effective treatment strategies. A contemporary view of alcohol addiction is that adaptations in glutamate (GLU) and dopamine (DA) transmission within regions of the striatum (key components of neurocircuitry that mediate motivated behavior) play a significant role in regulation of ethanol drinking behavior. While our current research efforts have focused on neurochemical adaptations in the ventral striatum (i.e., nucleus accumbens; NAc), recent evidence suggests that adaptations in GLU and DA transmission in the dorsolateral striatum (DLS) may play a prominent role in mediating the transition from controlled drinking to uncontrolled compulsive drinking that is characteristic of ethanol dependence. Accordingly, the overall objective of this proposal is to examine adaptations in GLU and DA transmission in dorsal striatum that may qualitatively or quantitatively differ from those in ventral striatum, as well as evaluate the influence of pharmacotherapeutics on voluntary ethanol drinking and neurochemical alterations that may underlie motivation to drink in dependent compared to nondependent animals. A guiding principle of the proposal is that ethanol dependence is associated with adaptations in GLU and DA transmission within dorsolateral striatum and that play an integral role in driving transition from moderate controlled drinking to uncontrolled excessive drinking. The research plan entails use of an established mouse model of ethanol dependence and relapse drinking along with in vivo microdialysis procedures to characterize changes in extracellular levels of GLU and DA in dorsal compared to ventral regions of the striatum that are associated with escalation of voluntary ethanol drinking in dependent mice compared to stable intake exhibited by nondependent mice. Additionally, these studies will provide new information on potential neuroanatomical sites and neurochemical mechanisms underlying the ability of pharmacological treatments to reduce excessive ethanol drinking associated with dependence, which could lead to new insights and approaches in the development of more effective pharmacotherapies for the treatment of alcoholism.