Cognitive Function in Alcohol Dependence and Protracted Withdrawal

描述（由申请人提供）：认知处理受损是成瘾的标志。抑制控制（冲动行为）的缺陷，对后果的评估（冲动选择）以及对强迫或习惯行为（认知灵活性）的无效逆转可以推动继续使用药物，尽管会产生不良后果。酒精研究中一个持续存在的问题是，既存认知障碍（即对问题饮酒的易感性）与诱导与皮质醇相关的认知障碍的相对影响。 反复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诱导的认知障碍的病因学提供重要的见解，并可以为机制研究和快速药物治疗筛选提供平台。使用类似于临床任务的行为范例，我们已经收集了初步证据，表明大鼠在长期间歇性饮酒的长期戒断过程中出现的冲动行为和冲动选择行为显著增加。这些认知障碍持续数周，并且可以通过已知的改善人类酗酒者认知功能的药理学操作来改善。基于这些发现和知识的神经机制，这些行为在大鼠中，我们假设，在额叶皮层区域的单胺和氨基酸信号的戒断相关失调有助于增加冲动和认知灵活性不足，在长期的酒精戒断。这一假设将通过三个具体目标进行检验。目标1将描述长期酒精戒断期间认知障碍的出现、性质和持续性。我们将使用一个新的5-选择连续表现任务（5C-CPT）和停止信号反应时间任务（SSRT）来探索冲动行为的不同方面。冲动选择行为将使用延迟折扣测试进行索引，认知灵活性将使用操作性空间逆转学习任务进行评估。目标2中的实验将采用体内微透析和生物化学方法来表征长期酒精戒断期间眶额和内侧前额叶皮质中的单胺和氨基酸功能。目的3将评估药物对改善戒断相关的冲动行为和冲动选择增加的疗效。

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.