Methamphetamine effect on cognitive flexibility

描述(申请人提供)：甲基苯丙胺(MAMPH)是一种高度上瘾的精神刺激剂。在美国的许多地区，大麻的使用频率仅次于酒精和大麻，经常超过海洛因和可卡因的滥用速度。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，但无论是在动物模型还是在人类中，mAMPH对认知灵活性的影响还没有进行系统的研究。认知灵活性对有机体的成功至关重要，指的是在一系列新环境下改变策略的能力。如果像目前认为的那样，mAMPH影响眶前皮质(OFC)的功能，那么mAMPH可能对灵活认知产生影响。此外，现在有证据表明5-羟色胺能调节这种灵活的认知，鉴于mAMPH滥用者(和mAMPH治疗动物)的神经元5-羟色胺完整性受到损害，这是一个及时的问题。我们建议使用对药物操作敏感的触摸屏操作程序来研究mAMPH对啮齿动物灵活认知的影响。我们对灵活认知的测量是逆转学习和消退，这是两个独立的任务，对OFC招募和5-羟色胺能调节都很敏感，并配备了一系列辅助措施，如动机、注意力和抑制控制。我们的长期目标是调和我们对帮助灵活认知的神经回路的理解与滥用药物的病理影响。为了开始实现我们的长期目标，我们提出了两个具体的目标：1)在未经治疗的大鼠中建立基线认知灵活性表现；2)比较暴饮式和递增神经保护剂量的mAMPH方案对认知灵活性和OFC的影响。这个项目的结果将加深我们对mAMPH对灵活认知过程的影响的了解，并提高我们识别治疗靶点的能力，以改善因滥用mAMPH而产生的糟糕决策。充其量，获救的认知灵活性可以帮助MAMPH成瘾者保持戒断。 公共卫生相关性：甲基苯丙胺是一种高度上瘾的精神刺激剂，也是一个日益令人关注的公共卫生问题，据记录，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.