Cognitive Function in Alcohol Dependence and Protracted Withdrawal

描述(由申请者提供)：认知处理能力受损是上瘾的标志。抑制控制的缺陷(冲动行为)、对后果的糟糕评估(冲动选择)以及对强迫或习惯性行为的无效逆转(认知灵活性)可能会促使继续使用药物，尽管会产生不利的后果。酒精研究中的一个持续存在的问题是，先前存在的认知障碍对问题饮酒的易感性与与皮质相关的认知障碍的诱导之间的相对影响 反复酒精中毒和戒断所造成的损害。在这方面，动物模型可以为了解酒精性认知障碍的病因提供重要的洞察力，并为机制研究和快速药物治疗筛选提供平台。使用类似于临床使用的任务的行为范式，我们收集了在长期间歇性饮酒过程中大鼠出现的冲动行为和冲动选择行为显着增加的初步证据。这些认知障碍会持续几周，并可以通过一种已知的改善人类酗酒者认知功能的药物操作来改善。基于这些发现和对支配这些行为的神经机制的了解，我们假设与戒断相关的额叶皮质区域单胺和氨基酸信号的失调导致了长时间酒精戒断时冲动的增加和认知灵活性的缺乏。这一假设将通过三个具体目标进行检验。目标1将描述长期戒酒过程中认知障碍的出现、性质和持续性。冲动性行为的不同方面将使用一种新颖的5-选择连续执行任务(5C-CPT)和停止信号反应时间任务(SSRT)来探索。冲动的选择行为将使用延迟折扣测试进行索引，认知灵活性将使用可操作的空间反转学习任务进行评估。AIM 2的实验将使用体内微透析和生化方法来表征长期酒精戒断时眼眶前额叶和内侧前额叶皮质中单胺和氨基酸的功能。目的3将评估药物对改善与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.