Thalamic Processes of Self Control in Cocaine Dependence

描述(由申请人提供)：强制寻求和吸食毒品是可卡因依赖的一个明显特征。自我控制能力受损是导致这种强制吸毒行为的原因之一。尽管有大量的行为证据表明可卡因依赖(PCD)患者的自控力受损，但这种缺陷背后的神经过程仍不清楚。特别是，PCD自我控制障碍的分子基础还没有被探索。目前的方案通过结合停止信号任务(SST)期间的功能磁共振成像(FMRI)和去甲肾上腺素转运体(NET)的正电子断层扫描(PET)来检查PCD患者的丘脑自我控制过程，填补了这一重要空白。具体地说，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试验评估，展示了与错误相关的皮质和皮质下活动的明显模式。特别是，错误相关的丘脑活动与PCD自我控制困难的主观报告有关。可卡因已知会影响去甲肾上腺素能神经传递，而丘脑是从脑干接受广泛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丘脑去甲肾上腺素能神经传递的改变，以及这种改变是否与PCD的自我控制能力受损和习惯性使用可卡因直接相关。为了解决这个问题，我们利用一个特定的净放射性配体-(S，S)-[11C]甲基瑞波西汀(11C-MRB)-来检查在停止信号任务中诱发的错误相关丘脑活动与戒断性PCD的净可利用性之间的关联。我们假设错误相关的丘脑活动与PCD的净利用度密切相关。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。这项新的研究将为我们进一步探索去甲肾上腺素能神经传递在预测PCD复发使用可卡因方面的作用提供关键数据。这项研究还将描绘有助于开发可卡因依赖的新药物治疗的分子机制的一个关键方面。公共卫生相关性：目前的提案通过结合功能成像和去甲肾上腺素转运体的分子成像来研究可卡因依赖患者冲动控制缺陷的神经过程。去甲肾上腺素转运体是调节去甲肾上腺素能神经传递的关键蛋白，受可卡因暴露的影响。这一潜在的结果将勾勒出分子机制的一个关键方面，这些机制有助于开发可卡因依赖的新药物疗法。

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.