Methamphetamine effect on cognitive flexibility

描述（由申请人提供）：甲基苯丙胺（mAMPH）是一种高度成瘾性的精神兴奋剂。在美国的许多地区，它是仅次于酒精和大麻的最常用毒品，经常超过海洛因和可卡因的滥用。尽管最近越来越多的研究致力于测量mAMPH对学习和记忆的影响，但在动物模型或人类中，mAMPH对认知灵活性的影响尚未进行系统的调查。认知灵活性对生物体的成功至关重要，它指的是在新环境下改变策略的能力。如果mAMPH像目前假设的那样影响眶额皮质（OFC）的功能，那么mAMPH可能对灵活认知有影响。此外，现在有证据表明5 -羟色胺能调节这种灵活的认知，并且考虑到神经5 -羟色胺完整性在mAMPH滥用者（和接受mAMPH治疗的动物）中受到损害，这是一个及时的问题。我们建议在啮齿类动物中使用基于触摸屏的敏感药理学操作程序来研究mAMPH对灵活认知的影响。我们对灵活认知的测量是逆向学习和消退，这是两个独立的任务，对OFC募集和血清素能调节都很敏感，并且配备了大量的动机、注意力和抑制控制的辅助测量。我们的长期目标是调和我们对神经回路的理解，使灵活的认知与药物滥用的病理影响相协调。为了开始实现我们的长期目标，我们提出了两个具体目标：1)建立未经治疗大鼠的基线认知灵活性表现；2)比较暴饮暴食方案和不断增加的神经保护剂量的mAMPH方案对认知灵活性和OFC的影响。这个项目产生的结果将增强我们对mAMPH对灵活认知过程的影响的理解，并提高我们确定治疗靶点的能力，以改善因mAMPH滥用而引起的不良决策。最好的情况是，恢复认知灵活性可以帮助mAMPH成瘾者保持戒断。

DESCRIPTION (provided by applicant): Methamphetamine (mAMPH) is a highly addictive psychostimulant. In many regions of the United States, it is second only to alcohol and marijuana as the most frequently used drug, often outpacing both heroin and cocaine abuse. Despite an increased number of studies recently devoting attention to measuring mAMPH effects on learning and memory, no systematic investigation has been conducted on mAMPH's impact on cognitive flexibility in either an animal model or in humans. Cognitive flexibility is of vital importance to the success of an organism and refers to the ability to shift strategy given a new set of circumstances. If mAMPH impacts functioning of the orbitofrontal cortex (OFC), as is currently posited, then mAMPH likely has an impact on flexible cognition. In addition, there is now evidence for serotonergic modulation of this flexible cognition and given that neuronal serotonin integrity is compromised in mAMPH abusers (and mAMPH-treated animals), this is a timely issue. We propose to study the effects of mAMPH on flexible cognition using a touch screen-based operant procedure sensitive to pharmacological manipulation in rodents. Our measures of flexible cognition are reversal learning and extinction, two separate tasks sensitive to both OFC recruitment and serotonergic modulation and that are well-equipped with a host of auxiliary measures of motivation, attention, and inhibitory control. Our long-term goal is to reconcile our understanding of the neural circuitry that subserves flexible cognition with the pathological effects of drugs of abuse. To begin to accomplish our long-term goal, two specific aims are proposed: 1) to establish baseline cognitive flexibility performance in untreated rats and 2) to compare the effects of a binge regimen and an escalating, neuroprotective dose regimen of mAMPH on cognitive flexibility and the OFC. Results arising from this project will enhance our understanding of the impact of mAMPH on flexible cognitive processes and increase our ability to identify therapeutic targets to ameliorate the poor decision making arising from mAMPH abuse. At best, a rescued cognitive flexibility could aid mAMPH addicts in remaining abstinent. Public Health Relevance: Methamphetamine is a highly addictive psychostimulant and a growing public health concern, with a record of nearly 1.4 million people over the age of 12 using methamphetamine in the United States in 2005. Those addicted to this substance make poor, disadvantageous choices and relapse often. The long-term goal of this project is to provide knowledge about the effects of methamphetamine on decision making and the brain.