Cognitive dysfunction and impaired inhibitory control in cocaine dependence

可卡因依赖的认知功能障碍和抑制控制受损

• 批准号: 8107622
• 负责人: CHARLES W BRADBERRY
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107622
• 关键词: Address; Animal Model; Area; Atlases; Behavioral; Brain imaging; Cell physiology; Cellular Structures; Chronic; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cognitive; Cognitive deficits; Control Animal; Deltastab; Discrimination; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Electrophysiology (science); Etiology; Event; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Impulsivity; Individual; Link; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mediating; Methodology; Modeling; Monitor; Monkeys; Motor; Neurons; Performance; Predisposition; Prefrontal Cortex; Primates; Principal Investigator; Psychostimulant dependence; Reporting; Research Design; Role; Self Administration; Self-Administered; Signal Transduction; Societies; Source; Stimulus; Structure; System; Task Performances; Temporal Lobe; Therapeutic; Treatment Protocols; Treatment outcome; addiction; base; clinically relevant; cocaine use; cognitive control; gray matter; in vivo; morphometry; nonhuman primate; preclinical study; programs; response; white matter

DESCRIPTION (provided by applicant): Cognitive dysfunction and impaired inhibitory control are hallmarks of addiction. The prefrontal and temporal cortices are essential to effective cognitive performance, and drug abuse is associated with significant structural deficits therein. A crucial unresolved question in clinical studies is whether structural and functional differences in cortex predate, or are consequent to drug use. This application proposes longitudinal structural MR imaging in a monkey model of addiction-related cognitive and inhibitory control deficits to address the role of drug use per se in structural and functional cortical differences seen in cocaine addiction. It also will examine single unit activity to determine what cellular changes could mediate an association of altered structure and function. Animal models are key to addressing questions about the etiology and cellular basis of addiction-related cognitive dysfunction. This is especially so for primate models that share structural and cognitive similarities to humans at the cortical level and that can exploit common methodologies such as brain imaging techniques used clinically. This application will employ a clinically relevant rhesus monkey self- administration model that shows impaired performance virtually identical to that seen clinically on the Stop Task, which is used to measure impaired inhibitory control, and which is supported by a well- defined circuitry identified in clinical and pre-clinical studies. Deficits in stimulus discrimination consistent with clinical reports have also been established. We will employ the monkey model to address these fundamental questions: 1) Do structural alterations in prefrontal and temporal cortex observed in cocaine users result from drug exposure per se, rather than a preexisting condition? 2) Within individuals, does the degree of cognitive impairment correlate with extent of structural change? 3) What are cellular correlates of cognitive dysfunction associated with cocaine use? The integration of a longitudinal application of clinically employed structural and cognitive assessments, along with single unit studies, will help establish the relationship between cocaine use, altered structure, and cellular mechanisms associated with cognitive dysfunction observed clinically. Drug addiction causes extensive human suffering and financial loss to society. Understanding the source and mechanisms of cognitive dysfunction that predicts treatment outcome may help develop therapeutic approaches that lessen harm from addiction.

描述（由申请人提供）：认知功能障碍和抑制性控制受损是成瘾的标志。前额叶和颞皮质对于有效的认知表现至关重要，药物滥用与其中的重大结构缺陷有关。临床研究中的一个至关重要的问题是皮质的结构和功能差异是否早于药物使用或造成药物使用。该应用提出在与成瘾相关的认知和抑制性控制缺陷的猴子模型中提出纵向结构MR成像，以解决药物使用本身在可卡因成瘾中看到的结构和功能性皮质差异中的作用。它还将检查单个单位活动，以确定哪些细胞变化可以介导结构和功能改变的关联。动物模型是解决有关与成瘾相关的认知功能障碍的病因和细胞基础问题的关键。对于在皮质水平上与人类具有结构和认知相似之处的灵长类动物模型尤其如此，并且可以利用诸如临床上使用的脑成像技术之类的常见方法。该应用将采用临床上相关的恒河猴自我给药模型，该模型显示出与临床上在停止任务上看到的相同的性能受损，该模型用于测量受损的抑制性控制，并由在临床和临床前研究中确定的良好定义的电路支持。还建立了与临床报告一致的刺激歧视缺陷。我们将采用猴子模型来解决这些基本问题：1）在可卡因使用者中观察到的前额叶和颞皮质的结构改变是由药物暴露本身而不是先前存在的情况而导致的吗？ 2）在个人内部，认知障碍的程度是否与结构变化的程度相关？ 3）与可卡因使用相关的认知功能障碍的细胞相关性是什么？纵向应用结构和认知评估以及单个单位研究的纵向应用的整合将有助于确定可卡因使用，改变结构的改变与与认知功能障碍相关的细胞机制之间的关系。吸毒成瘾会给社会带来广泛的人类苦难和经济损失。了解预测治疗结果的认知功能障碍的来源和机制可能有助于开发治疗方法，从而减少成瘾的伤害。