RC1 PHARMACOTHERAPY AND MECHANISMS OF ETHANOL DEPENDENCE AND RELAPSE DRINKING

RC1 药物治疗以及乙醇依赖和酗酒的机制

• 批准号: 8128127
• 负责人: HOWARD C. BECKER
• 金额: $ 24.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128127
• 关键词: Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Animals; Anticonvulsants; Antipsychotic Agents; Automobile Driving; Autoreceptors; Behavior; Brain; Characteristics; Chronic; Corpus striatum structure; Dependence; Development; Disease; Dopamine; Dorsal; Ethanol dependence; Exhibits; Funding; Glutamates; Goals; Habits; Heavy Drinking; Intake; Lead; Maintenance; Mediating; Medical; Microdialysis; Microinjections; Modeling; Motivation; Mus; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Play; Procedures; Property; Public Health; Quinpirole; Recording of previous events; Recurrent disease; Regulation; Relapse; Research; Rewards; Role; Site; Social Problems; Testing; Ventral Striatum; Work; alcohol exposure; alcohol relapse; alcohol research; alcoholism therapy; aripiprazole; attenuation; drinking; drinking behavior; driving behavior; effective therapy; extracellular; in vivo; insight; metabotropic glutamate receptor 2; motivated behavior; mouse model; neurochemistry; neurotransmission; novel; presynaptic; prevent; topiramate; transmission process; treatment center; treatment strategy

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.

酗酒是一种慢性复发性障碍，在美国仍然是一个严重的医学和社会问题，需要加大治疗力度。我们对饮酒动机潜在机制的了解取得进展，特别是推动从适度饮酒向更多过度和不受控制的饮酒转变的机制，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一种观点认为，纹状体(介导动机行为的神经回路的关键组成部分)内谷氨酸(GLU)和多巴胺(DA)传递的适应在调节酒精饮酒行为方面发挥着重要作用。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，但最近的证据表明，背外侧纹状体(DLS)的GLU和DA传递的适应可能在调节酒精依赖特征的从受控饮酒向失控强迫饮酒的转变中发挥重要作用。因此，这项建议的总体目标是检查背侧纹状体GLU和DA传递的适应性，可能在定性或定量上与腹侧纹状体不同，以及评估药物疗法对自愿饮酒和神经化学变化的影响，这些变化可能是依赖与非依赖动物饮酒动机的基础。该提案的指导原则是，酒精依赖与背侧纹状体内GLU和DA传递的适应有关，并在推动从适度控制饮酒向不受控制过度饮酒的转变中发挥不可或缺的作用。这项研究 PLAN需要使用已建立的酒精依赖和反复饮酒的小鼠模型以及体内微透析程序来表征与纹状体腹侧区域相比，背侧纹状体细胞外GLU和DA水平的变化，这些变化与依赖小鼠自愿饮酒的升级有关，而不依赖小鼠表现出稳定的摄入。此外，这些研究将提供潜在的神经解剖部位和神经化学机制的新信息，这些信息可能是药物治疗减少与依赖相关的过度饮酒的能力的基础，这可能导致在开发更有效的治疗酒精中毒的药物治疗方面的新见解和新方法。