Cognitive impact of cocaine cues and agonist treatment approaches

描述（由申请人提供）： 在可卡因使用者的临床研究中，注意力缺陷是突出的，并且可能导致与可卡因依赖相关的广泛的认知缺陷。了解这些认知缺陷的基础在临床上是重要的，因为认知表现和治疗结果之间的关系已经得到证实。两个分布的皮层网络以“反相关”的方式相互作用，以支持集中注意力的处理。背侧额顶叶系统在有目的的认知任务中被激活。另一个分布式网络，“默认模式网络”在集中认知任务期间从休息时的高代谢活动停用到较低水平。默认模式网络的失活受损与注意力缺失相关，并且具有注意力缺陷的临床人群显示默认模式网络的完整性受损和阶段性失活。多巴胺与注意力处理有关，最近的证据表明多巴胺转运蛋白与默认网络失活之间存在负相关。也有证据表明，人类可卡因使用者在短期戒断期间多巴胺能神经传递不足，部分原因是多巴胺转运蛋白上调。在本申请中，我们建议检查总体假设，即慢性可卡因使用后的注意力受损与集中注意力期间默认模式网络的失活不足相关，并且多巴胺能神经传递不足是受损默认网络失活的近因。我们将通过实现四个目标来研究这一假设：目标1）使用具有参数可变注意力需求的注意力任务来建立对照组和慢性可卡因自我管理组注意力受损的猴子的功能性脑成像研究的匹配表现。目的2）利用高分辨率microPET成像技术定量两组动物的多巴胺转运蛋白。目的3）使用局部葡萄糖代谢的microPET测量来确定慢性可卡因组在注意处理期间是否显示受损的默认模式网络失活。目的4）确定用低剂量的间接多巴胺激动剂安非他明治疗是否改善了注意力控制，同时改善了通过CMRglc测量的默认模式网络的失活。 公共卫生相关性： 正如吸毒成瘾和滥用毒品困扰着普通民众一样，武装部队的退伍军人也受到这些问题的影响。很明显，认知缺陷是成瘾的后果之一。由于认知技能可以预测患者对治疗的反应，因此了解成瘾相关缺陷的神经生物学非常重要。这些知识可能有助于学习如何通过帮助提高认知技能来治疗成瘾。这项申请寻求支持的研究，这将有助于我们了解，如果在特定的大脑网络的变化可能会导致认知缺陷，以及我们如何纠正这些变化。

DESCRIPTION (provided by applicant): Deficits in attention are prominent in clinical studies of cocaine users, and likely contribute to a broad range of cognitive deficits associated with cocaine dependence. Understanding the basis of these cognitive deficits is clinically important because of the demonstrated relationship between cognitive performance and treatment outcome. Two distributed cortical networks interact in an "anti- correlated" fashion in support of focused attentional processing. A dorsal frontoparietal system becomes activated during purposeful cognitive tasks. Another distributed network, the "default mode network" deactivates from a high metabolic activity at rest to a lower level during focused cognitive tasks. Impaired deactivation of that default mode network is associated with attentional lapses and clinical populations with attentional deficits show impaired integrity and phasic deactivation of the default mode network. Dopamine is implicated in attentional processing, and recent evidence demonstrates an inverse correlation between the dopamine transporter and default network deactivation. There is also evidence for inadequate dopaminergic neurotransmission in human cocaine users during short term withdrawal, in part from an up-regulated dopamine transporter. In the present application, we propose to examine the overarching hypothesis that impaired attention following chronic cocaine use is associated with inadequate deactivation of the default mode network during focused attention, and that insufficient dopaminergic neurotransmission is a proximate cause of the impaired default network deactivation. We will investigate this hypothesis by accomplishing four aims: Aim 1) Use an attentional task with parametrically variable attentional demand to establish matched performance for functional brain imaging studies in a control, and a chronic cocaine self-administering group of monkeys with impaired attention. Aim 2) Quantify the dopamine transporter in the two groups of animals using high resolution microPET imaging. Aim 3) Determine if the chronic cocaine group shows impaired default mode network deactivation during attentional processing using microPET measures of regional glucose metabolism. Aim 4) Determine if treatment with a low dose of the indirect dopamine agonist amphetamine improves attentional control concomitant with improved deactivation of the default mode network measured by CMRglc. PUBLIC HEALTH RELEVANCE: Just as addiction and drug abuse afflict the general population, veterans of the armed forces are also affected by these problems. It has become apparent that cognitive deficits are one consequence of addiction. Because cognitive skills predict how well patients respond to therapy, it is important to understand the neurobiology of addiction related deficits. This knowledge may help in learning how to treat addiction via helping increase cognitive skills. This application seeks support for studies that will help us to understand if alterations in particular brain networks may be contributing to cognitive deficits, and how we might correct those alterations.