The effect of methylphenidate use and abuse on dopamine system kinetics

描述（由申请人提供）：哌醋甲酯（MPH，利他林）是一种兴奋剂，通常用于治疗注意力缺陷/多动症。静脉注射（i. v.）近年来，MPH管理变得越来越普遍，鉴于缺乏对其行为和神经生物学后果的研究，这是一个令人担忧的趋势。当通过相同途径给药时，MPH的主观效应与可卡因（COC）和苯丙胺（AMPH）无法区分。MPH是一种AMPH类似物，可抑制多巴胺（DA）和去甲肾上腺素转运蛋白，尽管MPH不是转运蛋白的底物，但已显示其在高浓度下释放DA（Heal et al，2009）。因此，MPH具有DAT相互作用，部分类似于其他精神兴奋剂，如COC和AMPH。已经检查了实验者提供的MPH对DA神经生物学的影响的研究是不一致的，并且不同的范例可以导致不同的，有时是相反的，效果。拟议的研究将调查MPH摄入量的升级，这是一个模型，从娱乐使用到成瘾状态的过渡。除了DAT/精神兴奋剂相互作用的长期改变外，还将确定伴随MPH摄入量增加的潜在神经化学改变。本研究将通过检查MPH、COC和AMPH的奖励和强化效应来评估这些神经化学变化的行为相关性。最后，使用转基因DAT过表达小鼠，一个假设的机制MPH SA诱导增加精神兴奋剂神经化学效价，增强疗效，奖励将进行测试。 公共卫生相关性：NRSA提出的研究解决了公众健康的一个主要问题，哌醋甲酯（MPH）滥用的神经生物学后果。许多儿童被处方MPH用于治疗ADHD，此外，2008年有480万人报告滥用这种容易获得的精神兴奋剂（SAMHSA，2008）。令人痛心的是，许多报告和病例研究记录了静脉注射MPH。目前的MPH给药模型不模拟人类使用该化合物，因此，对MPH滥用的行为和神经生物学后果知之甚少。通过研究长期使用的MPH自我管理，一个模式，从滥用到成瘾的人类转换，我们将能够确定相关的改变后，发生延长使用药物。此外，通过确定MPH自我管理对其他精神兴奋剂的奖励和强化作用的影响，我们将能够确定可能是最危险的模式，在人类中产生精神兴奋剂滥用。

DESCRIPTION (provided by applicant): Methylphenidate (MPH, Ritalin) is a stimulant commonly prescribed for the treatment of attention- deficit/hyperactivity disorder. Intravenous (i.v.) MPH administration has become increasingly prevalent in recent years, and is an alarming trend given the lack of research on its behavioral and neurobiological consequences. The subjective effects of MPH are indistinguishable from both cocaine (COC) and amphetamine (AMPH) when administered via the same route. MPH is an AMPH analog that inhibits the dopamine (DA) and norepinephrine transporters, and although MPH is not a substrate for the transporter, it has been shown to release DA at high concentrations (Heal et al, 2009). Thus, MPH possesses DAT interactions that are similar, in part, with other psychostimulants such as COC and AMPH. The studies that have examined the effects of experimenter-delivered MPH on DA neurobiology are inconsistent, and different paradigms can cause different, sometimes opposite, effects. The proposed studies will investigate escalation of MPH intake, a paradigm that models the transition from recreational use to an addictive state. The underlying neurochemical alterations that accompany increases in intake of MPH will be identified in addition to long-term alterations DAT/psychostimulant interactions. This research will then assess the behavioral relevance of these neurochemical alterations by examining the rewarding and reinforcing effects of MPH, COC, and AMPH. Finally, using transgenic DAT over-expressing mice, a hypothesized mechanism for MPH SA-induced increases in psychostimulant neurochemical potency, reinforcing efficacy, and reward will be tested. PUBLIC HEALTH RELEVANCE: The research proposed in this NRSA addresses a major concern for public health, the neurobiological consequences of methylphenidate (MPH) abuse. Many children are prescribed MPH for the treatment of ADHD, and in addition, 4.8 million people reported abusing the easily attainable psychostimulant in 2008 (SAMHSA, 2008). There are distressingly, numerous reports and case studies documenting intravenous administration of MPH. The current models of MPH administration do not mimic human use of the compound and thus, little is known about the behavioral and neurobiological consequences of MPH abuse. By studying long access MPH self-administration, a paradigm that models the switch from abuse to addiction in humans, we will be able to determine relevant alterations that occur after extended use of the drug. In addition, by determining the effects of MPH self-administration on the rewarding and reinforcing effects of other psychostimulants, we will be able to identify the patterns that may be most dangerous in producing psychostimulant abuse in humans.