NEUROCHEMICAL DETERMINANTS OF MA-INDUCED COGNITIVE DEFICITS

依赖于甲基苯丙胺（MA）的人类受试者表现出功能和结构上的差异。 额纹状体回路异常，最有可能导致滥用MA的行为后遗症。 关于MA滥用导致的特定神经化学适应以及它们是如何发生的，我们仍然知之甚少。 直接导致神经行为功能受损项目3将采用非人类灵长类动物模型， MA依赖性，以探索导致反应抑制受损的神经化学机制（如 由逆转学习任务索引），其由药物暴露引起（目标1）。使用体内和体外 脑儿茶酚胺功能的措施，我们将产生关于分子和神经化学的见解， 这些适应直接导致了项目1中揭示的功能性大脑异常。 这些研究将在两个重要方面得到扩展。首先，我们将探讨 莫达非尼的作用，一种改善人类反应抑制的药物， 机制，在治疗兴奋剂依赖方面具有治疗功效。我们会把莫达非尼 控制和MA经验的猴子，并将测试假设，这种代理发挥促认知的影响 通过间接刺激α-2肾上腺素能受体（Aim 2）。这些复杂的药理学实验 这些在人类受试者中不容易进行，将使我们能够定义一种作用机制， 莫达非尼，反过来，将提供一个更好的了解莫达非尼如何产生特定的行为， 项目1和项目2中正在研究的影响。我们的最终目标是确定更具体的药理学靶点， 干预措施。如上所述，莫达非尼可能产生a-2肾上腺素能受体的间接刺激 现在有多方面的证据支持直接的α-2肾上腺素受体激动剂可以改善 认知.因此，我们将进行实验来验证选择性激活a-2受体 促进MA暴露猴的反应抑制（目的3）;这些结果将与 亚型特异性多巴胺受体激动剂或拮抗剂，基于支持其 参与逆向学习。这些实验有可能推动药物治疗的新阶段 在成熟的翻译研究中心进行评估。通过这些目标，项目3建议提供一个 临床数据的机制基础，并指导临床人群的未来假设检验。

Human subjects who are dependent on methamphetamine (MA) exhibit functional and structural abnormalities within frontostriatal circuitry that most likely contribute to behavioral sequelae of MA abuse. Still little is known about the specific neurochemical adaptations that result from MA abuse and how they contribute directly to impaired neurobehavioral function. Project 3 will employ a non-human primate model of MA dependence to explore the neurochemical mechanisms contributing to impaired response inhibition (as indexed by a reversal learning task) that results from drug exposure (Aim 1). Using both in vivo and ex vivo measures of brain catecholamine function, we will generate insights about the molecular and neurochemical adaptations that contribute directly to functional brain abnormalities revealed in Project 1. These studies will then be extended in two important ways. First, we will explore the mechanisms of action of modafinil, a drug that improves response inhibition in humans and which may, through this mechanism, have therapeutic efficacy in the treatment of stimulant dependence. We will deliver modafinil to control and MA-experienced monkeys and will test the hypothesis that this agent exerts pro-cognitive effects by indirect stimulation of a-2 adrenergic receptors (Aim 2). These complex pharmacological experiments, which are not readily performed in human subjects, will allow us to define a mechanism of action for modafinil and will, in turn, provide a greater understanding of how modafinil produces specific behavioral effects being studied in Projects 1 and 2. Our final goal is to identify more specific targets for pharmacological interventions. As noted above, modafinil may produce indirect stimulation of a-2 adrenergic receptors and multiple lines of evidence now supports the notion that direct a-2 adrenoceptor agonists can improve cognition. We will therefore conduct experiments to test the idea that selective activation of a-2 receptors facilitates response inhibition in MA-exposed monkeys (Aim 3); these results will be compared with effects of subtype-specific dopamine receptor agonists or antagonists, based upon direct evidence supporting their involvement in reversal learning. These experiments have the potential to drive a new phase of medication evaluation in a mature translational research center. Through these Aims, Project 3 proposes to provide a mechanistic foundation for clinical data and to direct future hypothesis testing in clinical populations.