Thalamic Processes of Self Control in Cocaine Dependence

描述（由申请人提供）：强制寻求和消费毒品是可卡因依赖的一个决定性特征。自我控制能力的损害导致了这种强制使用药物的行为。尽管有大量的行为证据表明可卡因依赖（PCD）患者的自我控制受损，但这种缺陷背后的神经过程仍不清楚。特别是，PCD中自我控制障碍的分子基础尚未被探索。目前的建议填补了这一重要空白，通过在停止信号任务（SST）期间结合功能性磁共振成像（fMRI）和正电子断层扫描（PET）成像的去甲肾上腺素转运体（NET）来检查PCD中自我控制的丘脑过程。具体来说，我们之前对SST的研究，允许对错误处理的神经过程进行一次又一次的评估，证明了与错误相关的皮层和皮层下活动的独特模式。特别是，错误相关的丘脑活动与PCD患者自我控制困难的主观报告有关。已知可卡因会影响去甲肾上腺素能神经传递，而丘脑是接收来自脑干的大量去甲肾上腺素能输入的关键区域。因此，一个关键的问题是，长期使用可卡因是否导致了丘脑去甲能神经传递的改变，以及这种改变是否与PCD患者的自我控制受损和习惯性使用可卡因直接相关。为了解决这个问题，我们利用特定的NET放射性配体- (S，S)-[11C]甲基利波西汀(11C- mrb)-来研究在停止信号任务期间引起的错误相关丘脑活动与戒断性PCD中NET可用性之间的关系。我们假设错误相关的丘脑活动与PCD的NET可用性密切相关。因此，这些潜在的结果将提供重要的知识，补充我们对可卡因依赖的多巴胺能过程的理解。这项新研究将为我们进一步探索去甲肾上腺素能神经传递改变在预测PCD患者可卡因使用复发中的作用提供关键数据。这项研究还将描述分子机制的一个关键方面，有助于开发新的药物治疗可卡因依赖。公共卫生相关性：目前的建议通过结合去甲肾上腺素转运体的功能成像和分子成像来研究冲动控制缺陷的神经过程，去甲肾上腺素转运体是一种调节去甲肾上腺素能神经传递的关键蛋白质，受可卡因暴露的影响。潜在的结果将描绘分子机制的一个关键方面，有助于开发新的药物治疗可卡因依赖。

DESCRIPTION (provided by applicant): Compulsory drug seeking and consumption is a defining feature of cocaine dependence. Impairment in self control contributes to such compulsory drug using behaviors. Despite abundant behavioral evidence for impaired self control in patients with cocaine dependence (PCD), the neural processes underlying such a deficit remain unclear. In particular, the molecular underpinnings of the impairment in self control in PCD has not been explored. The current proposal fills this important gap by combining functional magnetic resonance imaging (fMRI) during a stop signal task (SST) and positron tomography (PET) imaging of the norepinephrine transporter (NET) to examine the thalamic processes of self control in PCD. Specifically, our previous studies of the SST, which allows trial by trial evaluation of the neural processes of error processing, demonstrates a distinct pattern of error-related cortical and subcortical activities. In particular, error-related thalamic activity is associated with subjective report of difficulty in self control in PCD. Cocaine is known to influence noradernergic neurotransmission, and the thalamus is a key region that receives extensive noradrenergic inputs from the brain stem. A critical question thus is whether prolonged cocaine use has resulted in altered noradernergic neurotransmission in the thalamus and whether such alterations are directly associated with impaired self control and habitual cocaine use in PCD. To address this issue, we take advantage of a specific NET radioligand - (S,S)-[11C]Methylreboxetine (11C-MRB) - to examine the association between error-related thalamic activity evoked during the stop signal task and the NET availability in abstinent PCD. We hypothesize that error-related thalamic activity robustly correlate with NET availability in PCD. These potential results would thus provide important knowledge that complements our understanding of dopaminergic processes of cocaine dependence. This novel study would provide critical data for us to further explore the role of altered noradrenergic neurotransmssion in predicting relapse to cocain use in PCD. This study would also delineate a critical aspect of molecular mechanisms instrumental to the development of novel pharmacotherapy of cocaine dependence. PUBLIC HEALTH RELEVANCE: The current proposal investigates the neural processes of impulse control deficits by combining functional imaging and molecular imaging of the norepinephrine transporter - a key protein that regulates noradrenergic neurotransmission, which is affected by cocaine exposure - in cocaine dependent patients. The potential results would delineate a critical aspect of molecular mechanisms instrumental to the development of novel pharmacotherapy of cocaine dependence.