Cognitive dysfunction and impaired inhibitory control in cocaine dependence

描述（由申请人提供）：认知功能障碍和抑制控制受损是成瘾的标志。前额叶和颞叶皮层对于有效的认知表现是必不可少的，药物滥用与其中的显著结构缺陷有关。临床研究中一个关键的未解决的问题是，大脑皮层的结构和功能差异是否早于药物使用，或者是药物使用的结果。本申请提出了在成瘾相关认知和抑制控制缺陷的猴模型中进行纵向结构MR成像，以解决可卡因成瘾中所见的结构和功能皮质差异中药物使用本身的作用。它还将检查单个单位的活动，以确定哪些细胞变化可以介导改变的结构和功能的关联。动物模型是解决成瘾相关认知功能障碍的病因学和细胞基础问题的关键。对于灵长类动物模型来说尤其如此，这些模型在皮层水平上与人类具有结构和认知相似性，并且可以利用临床使用的脑成像技术等常见方法。本申请将采用临床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中观察到的几乎相同的受损性能，该模型用于测量受损的抑制控制，并得到临床和临床前研究中确定的明确电路的支持。与临床报告一致的刺激识别缺陷也已建立。我们将使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叶皮层的结构改变是否是由于药物暴露本身，而不是预先存在的条件？2)在个体内部，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？整合临床采用的结构和认知评估的纵向应用，沿着单一单元研究，将有助于建立可卡因使用、结构改变和与临床观察到的认知功能障碍相关的细胞机制之间的关系。吸毒成瘾给人类造成广泛的痛苦，并给社会造成经济损失。了解认知功能障碍的来源和机制，预测治疗结果可能有助于开发减少成瘾危害的治疗方法。

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.