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

基本信息

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
项目类别：
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

项目摘要

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.

酒精中毒是一种慢性复发障碍，在美国仍然是严重的医学和社会问题，需要加强努力来治疗它。我们对饮酒动机的基本机制的理解的进步，尤其是推动从中等饮酒过渡到更过量和不受控制的机制，这是制定新的，更有效的治疗策略的关键。当代酒精成瘾的看法是，纹状体区域内的谷氨酸（GLU）和多巴胺（DA）的适应性（DA）（DA）传播（介导动机行为的神经记录的关键组成部分）在调节乙醇饮用行为的调节中起着重要作用。虽然我们目前的研究工作集中在腹纹状体的神经化学适应（即，八核； NAC），但最近的证据表明，在背外纹状体（DLS）中GLU和DA传播的适应性可能在从受控的饮酒到无形的饮酒中介导的饮酒中的特征是在介导的饮酒中扮演重要的作用。因此，该提案的总体目的是检查背纹状体中GLU和DA传播的适应性，这些适应性可能与腹侧纹状体的质量或定量上不同，并评估药物治疗剂对自愿性乙醇饮酒和神经化学变化的影响，而与依赖于Nondondentent的动物相比，可能会激励饮酒。该提案的指导原则是，乙醇依赖性与背外侧纹状体内GLU和DA传播的适应性有关，并且在推动从中等控制的饮酒到不受控制的过量饮酒的过渡中起着不可或缺的作用。研究计划需要使用既定的乙醇依赖性小鼠模型和复发饮用，以及体内微透析程序，与质谱升级相比，与稳定的小鼠相比，与稳定的乙醇饮酒相比，背侧的GLU和DA的细胞外glu和DA的变化与稳定的乙醇饮酒有关。此外，这些研究将提供有关潜在的神经解剖部位和神经化学机制的新信息，该机制是药理治疗能力减少与依赖性相关的过度乙醇饮酒能力的能力，这可能会导致新的见解和方法在开发更有效的药物治疗药物治疗酒精中毒的药物治疗方面。