The effect of methylphenidate use and abuse on dopamine system kinetics

哌醋甲酯的使用和滥用对多巴胺系统动力学的影响

• 批准号: 8446692
• 负责人: Erin Calipari
• 金额: $ 2.11万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-12-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446692
• 关键词: Abuse Reporting; Acute; Address; Affect; Amphetamines; Attention deficit hyperactivity disorder; Behavioral; Case Study; Characteristics; Child; Cocaine; Data; Dopamine; Dose; Drug usage; Exhibits; Human; In Vitro; Intake; Intravenous; Kinetics; Long-Term Effects; Measures; Membrane; Methamphetamine; Methylphenidate; Modeling; Mus; National Research Service Awards; Neurobiology; Nomifensine; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Psychological reinforcement; Public Health; Reporting; Research; Rewards; Ritalin; Route; Self Administration; Surface; Testing; Time; Transgenic Organisms; United States Substance Abuse and Mental Health Services Administration; Western Blotting; Work; addiction; analog; crosslink; density; dopamine system; dopamine transporter; intravenous administration; methylphenidate abuse; neurochemistry; noradrenaline transporter; preference; psychostimulant; response; stimulant abuse; trafficking; trend; uptake

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.

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给药变得越来越普遍，并且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 & Zellweger，2006; Shaw等人，2008; J. 2008; Teter等人，2006年）。当通过相同途径给药时，MPH的主观效应与可卡因（COC）和安非他明（AMPH）两者不可区分（罗森等人，1985; Silverman和Ho，1980; Rush和Baker，2001）。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。然后，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诱导的增加精神兴奋剂神经化学效价，增强疗效，和奖励将进行测试。