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/多动障碍。静脉注射。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（DeSantis等人，2008；Gautschi和Zellweger, 2006； Shaw等人，2008；Teter等人，2006）。当通过同一途径给药时，MPH的主观效应与可卡因（COC）和安非他明（AMPH）没有区别（Rosen等人，1985；Silverman和Ho, 1980； Rush和Baker， 2001）。MPH是一种抑制多巴胺（DA）和去甲肾上腺素转运体的AMPH类似物，尽管MPH不是转运体的底物，但它已被证明可以释放高浓度的DA （Heal et al, 2009）。因此，MPH与其他精神兴奋剂如COC和AMPH具有部分相似的DAT相互作用。实验人员传递的MPH对DA神经生物学的影响的研究是不一致的，不同的范式可能导致不同的，有时是相反的效果。拟议的研究将调查MPH摄入量的增加，这是一个模拟从娱乐使用到成瘾状态过渡的范例。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的奖励和强化作用来评估这些神经化学改变的行为相关性。最后，使用转基因过表达DAT的小鼠，将测试MPH sa诱导的精神兴奋剂神经化学效力，强化功效和奖励增加的假设机制。

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 (DeSantis et al, 2008; Gautschi & Zellweger, 2006; Shaw et al., 2008; Teter et al., 2006). The subjective effects of MPH are indistinguishable from both cocaine (COC) and amphetamine (AMPH) when administered via the same route (Rosen et al., 1985; Silverman and Ho, 1980; Rush and Baker, 2001). 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.