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: 8255196
• 负责人: Erin Calipari
• 金额: $ 4.22万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255196
• 关键词: Abuse Reporting; Acute; Address; Affect; Amphetamines; Attention deficit hyperactivity disorder; Behavioral; Case Study; Characteristics; Child; Cocaine; Data; Disease; Dopamine; Dose; Drug usage; Exhibits; Human; Hyperactive behavior; 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. 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.

描述(申请人提供)：哌醋甲酯(mph，利他林)是一种常用的兴奋剂，用于治疗注意力缺陷/多动障碍。静脉注射(静脉注射)近年来，公共卫生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。当通过相同的途径给药时，mph的主观影响与可卡因(Coc)和苯丙胺(Amph)没有区别。MPH是一种AMPH类似物，它抑制多巴胺(DA)和去甲肾上腺素转运蛋白，虽然MPH不是转运蛋白的底物，但已被证明在高浓度下释放DA(Heal等人，2009年)。因此，MPH具有DAT相互作用，部分类似于其他精神刺激剂，如COC和AMPH。研究了实验者提供的公共卫生对DA神经生物学的影响的研究是不一致的，不同的范例可能会导致不同的，有时相反的影响。拟议的研究将调查公共卫生小时摄入量的升级，这是一个模型，模拟了从娱乐使用到上瘾状态的转变。除了DAT/精神刺激剂的长期改变外，还将确定伴随MPH摄入量增加的潜在神经化学改变。然后，这项研究将通过检查mph、COC和amph的奖赏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过度表达的小鼠，将测试一种假设的机制，即MPH SA诱导的精神刺激神经化学效力、增强效力和奖励的增加。 公共卫生相关性：这项NRSA中提出的研究解决了公众健康的一个主要问题，即滥用哌醋甲酯(MPH)的神经生物学后果。许多儿童被开出治疗ADHD的mph处方，此外，2008年有480万人报告滥用这种容易获得的精神刺激剂(SAMHSA，2008)。令人担忧的是，有大量的报告和案例研究记录了静脉给药的公共卫生。目前的mph给药模式并不能模拟人类对这种化合物的使用，因此，人们对滥用mph的行为和神经生物学后果知之甚少。通过研究长时间接触mph自我管理，这是一种模拟人类从滥用到成瘾的模式，我们将能够确定延长药物使用后发生的相关变化。此外，通过确定公共卫生标准自我给药对其他精神刺激剂的奖励和强化效果的影响，我们将能够识别在人类中产生精神刺激性虐待可能最危险的模式。