Cognitive Function in Alcohol Dependence and Protracted Withdrawal

酒精依赖和长期戒断的认知功能

基本信息

批准号：
9303764
负责人：
Remi Martin-Fardon
金额：
$ 38.7万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303764
关键词：
Abstinence Acetylcholine Acetylcysteine Alcohol abuse Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Intoxication Alcoholism Alcohols Amino Acids Animal Model Behavior Behavioral Behavioral Paradigm Behavioral inhibition Biochemical Choice Behavior Chronic Clinical Cognitive Complement Consumption Data Deltastab Dose Drug usage Etiology Evaluation Functional disorder Glutamates Heavy Drinking Human Impaired cognition Impairment Impulsivity Individual Investigation Knowledge Measures Medial Mediating Messenger RNA Microdialysis Nature Neurophysiology - biologic function Neurotransmitters Performance Pharmaceutical Preparations Pharmacology Pharmacotherapy Predisposition Prefrontal Cortex Rattus Reaction Time Reversal Learning Rodent Model Sampling Serotonin Signal Transduction Speed Task Performances Testing Therapeutic Treatment Efficacy Western Blotting Withdrawal addiction adverse outcome alcohol research atomoxetine base cognitive function design discount discounting drinking experimental study extracellular flexibility gabapentin gamma-Aminobutyric Acid improved in vivo indexing insight learned behavior monoamine neurochemistry neuromechanism neurophysiology novel performance tests pre-clinical problem drinker public health relevance quetiapine receptor receptor expression response screening

项目摘要

DESCRIPTION (provided by applicant): Impaired cognitive processing is a hallmark of addiction. Deficits in inhibitory control (impulsive action), poor evaluation of consequences (impulsive choice) and ineffective reversal of compulsive or habitual behaviors (cognitive flexibility) can propel continued drug use despite adverse consequences. A persistent question in alcohol research regards the relative influence of pre-existing cognitive disruptions that confe susceptibility to problem drinking versus the induction of cognitive impairment related to cortical damage induced by repeated alcohol intoxication and withdrawal. In this regard animal models can provide important insight into the etiology of alcohol-induced cognitive impairment and can provide a platform for mechanistic studies and rapid pharmacotherapy screening. Using behavioral paradigms analogous to clinically employed tasks we have gathered preliminary evidence of significant increases in impulsive action and impulsive choice behaviors that emerge in rats during protracted withdrawal from long-term intermittent alcohol consumption. These cognitive impairments persist for several weeks, and can be ameliorated by a pharmacological manipulation known to improve cognitive function in human alcoholics. Based on these findings and knowledge of the neural mechanisms governing these behaviors in rats we hypothesize that withdrawal-associated dysregulation of monoamine and amino acid signaling in frontal cortical regions contributes to increased impulsivity and deficient cognitive flexibility during protracted alcohol withdrawal. This hypothesis will be tested through three Specific Aims. Aim 1 will characterize the emergence, nature and persistence of cognitive disruption during protracted alcohol withdrawal. Different facets of impulsive action will be explored using a novel 5-Choice Continuous Performance Task (5C-CPT) and the Stop Signal Reaction Time task (SSRT). Impulsive choice behavior will be indexed using the Delay Discount Test, and cognitive flexibility will be assessed using an operant spatial reversal learning task. The experiments in Aim 2 will employ in vivo microdialysis and biochemical approaches to characterize monoamine, and amino acid function in the orbitofrontal and medial prefrontal cortices during protracted alcohol withdrawal. Aim 3 will evaluate the efficacy of pharmacologic agents for ameliorating withdrawal-associated increases in impulsive action and impulsive choice.

描述（由申请人提供）：认知处理受损是成瘾的标志。抑制性控制的缺陷（冲动行动），对后果的评估不佳（冲动性选择）和强迫性或习惯行为的无效逆转（认知灵活性）仍可以推动尽管不良后果，但仍可以继续使用毒品。酒精研究中的一个持续问题认为，先前存在的认知破坏的相对影响，即对饮酒的易感性与诱导与皮质相关的认知障碍的敏感性反复的酒精中毒和戒断引起的损害。在这方面，动物模型可以为酒精引起的认知障碍的病因提供重要的见解，并可以为机械研究和快速药物治疗筛查提供一个平台。使用类似于临床采用任务的行为范式，我们收集了初步证据，这些证据表明，在长期从长期间歇性饮酒中退出期间，大鼠出现了冲动行动和冲动性选择行为的显着增加。这些认知障碍持续数周，可以通过已知改善人类酒精中毒的认知功能的药理操作来改善。基于这些发现和对大鼠中这些行为的神经机制的了解，我们假设额叶皮质区域中单胺和氨基酸信号传导的戒断相关性失调促进了脉冲戒断期间的冲动性和缺陷的认知柔韧性。该假设将通过三个特定目标进行检验。 AIM 1将表征旷日持久的酒精戒断期间认知破坏的出现，性质和持久性。使用新颖的5选择连续性能任务（5C-CPT）和停止信号反应时间任务（SSRT），将探索冲动动作的不同方面。冲动选择行为将使用延迟折扣测试进行索引，并将使用操作空间逆转学习任务评估认知灵活性。 AIM 2中的实验将采用体内微透析和生化方法来表征单胺的表征，而在戒酒期间，在眶额和内侧前额叶皮层中的氨基酸功能。 AIM 3将评估药理学剂对脉冲作用和冲动选择的戒断相关增长的疗效。