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药物，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，还没有对mAMPH对认知灵活性的影响进行系统的研究。认知灵活性对一个有机体的成功至关重要，它指的是在一系列新的情况下改变策略的能力。如果mAMPH影响眶额皮质（OFC）的功能，就像目前假设的那样，那么mAMPH可能对灵活认知有影响。此外，现在有证据表明这种灵活认知的神经元5-羟色胺能调节，并且鉴于mAMPH滥用者（和mAMPH治疗的动物）中神经元5-羟色胺完整性受损，这是一个及时的问题。我们建议研究mAMPH对灵活认知的影响，使用基于触摸屏的操作程序敏感的药理学操作在啮齿动物。我们的灵活认知的措施是逆转学习和灭绝，两个独立的任务敏感的OFC招聘和神经元能调制，并配备了大量的辅助措施的动机，注意力和抑制控制。我们的长期目标是将我们对有助于灵活认知的神经回路的理解与滥用药物的病理影响相协调。为了开始实现我们的长期目标，提出了两个具体目标：1）在未治疗的大鼠中建立基线认知灵活性表现和2）比较mAMPH的暴饮暴食方案和递增的神经保护剂量方案对认知灵活性和OFC的影响。该项目的结果将增强我们对mAMPH对灵活认知过程的影响的理解，并提高我们识别治疗靶点的能力，以改善mAMPH滥用引起的不良决策。最好的情况是，挽救认知灵活性可以帮助mAMPH成瘾者保持禁欲。 公共卫生相关性：甲基苯丙胺是一种高度成瘾的精神兴奋剂，是一个日益严重的公共卫生问题，2005年美国有近140万12岁以上的人使用甲基苯丙胺。那些对这种物质上瘾的人会做出糟糕的、不利的选择，并且经常复发。该项目的长期目标是提供有关甲基苯丙胺对决策和大脑影响的知识。

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.