Cognitive impact of cocaine cues and agonist treatment approaches

描述(由申请人提供)： 注意力缺陷在可卡因使用者的临床研究中是突出的，并可能导致与可卡因依赖有关的广泛认知缺陷。了解这些认知缺陷的基础在临床上很重要，因为认知表现和治疗结果之间的关系已经得到证实。两个分布的大脑皮层网络以“反相关”的方式相互作用，以支持集中注意力的处理。在有目的的认知任务中，额顶背侧系统被激活。另一种分布式网络是“默认模式网络”，在专注的认知任务中，“默认模式网络”会从静止的高代谢活动停用到较低的水平。缺省模式网络失活受损与注意力疏忽相关，且具有注意力缺陷的临床人群表现出缺省模式网络的完整性受损和阶段性失活。多巴胺与注意加工有关，最近的证据表明，多巴胺转运蛋白和默认网络失活之间存在负相关。也有证据表明，在短期戒毒过程中，人类可卡因使用者的多巴胺能神经传递不足，部分原因是多巴胺转运蛋白上调。在目前的应用中，我们建议检验最重要的假设，即长期使用可卡因后注意力受损与集中注意期间默认模式网络的不充分失活有关，并且多巴胺能神经传递不足是受损的默认网络失活的直接原因。我们将通过实现四个目标来研究这一假说：目的1)使用一个具有参数可变的注意需求的注意任务，在一个对照组和一个长期服用可卡因的注意力受损的猴子组中，建立与脑功能成像研究相匹配的表现。目的2)利用高分辨率的microPET成像技术对两组动物体内的多巴胺转运体进行定量。目的3)应用microPET局部糖代谢测量，确定慢性可卡因组在注意加工过程中是否表现出默认模式网络失活受损。目的4)确定小剂量间接多巴胺激动剂苯丙胺治疗是否改善了注意力控制，同时改善了CMRglc测量的默认模式网络的失活。 公共卫生相关性： 正如毒瘾和药物滥用困扰着普通民众一样，军队的退伍军人也受到这些问题的影响。很明显，认知缺陷是上瘾的后果之一。因为认知技能可以预测患者对治疗的反应如何，所以了解与成瘾相关的缺陷的神经生物学是很重要的。这些知识可能有助于学习如何通过提高认知技能来治疗成瘾。这个应用程序寻求对研究的支持，这些研究将帮助我们了解特定大脑网络的变化是否可能导致认知缺陷，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.