Methylphenidate, Serotonin and Dopamine Interactions

描述（由申请人提供）：临床使用哌醋甲酯（MPH，利他林）治疗注意缺陷/多动障碍是广泛的，并且有一个日益增长的MPH滥用问题，特别是在大学年龄的成年人中。大学生使用MPH非医疗，主要是为了提高成绩，熬夜学习或获得快感。此外，所有年龄段的成年人都在使用标签外的高剂量MPH来增强能量和认知能力。MPH的滥用剂量是推荐临床使用剂量的2-10倍，然而，对于长期暴露于这些MPH剂量的神经生物学效应知之甚少。我们的实验室最近在小鼠身上发现了慢性高剂量MPH治疗的一个意想不到的后果。我们发现对氟西汀的行为和神经化学反应发生了质的转变。氟西汀是一种5-羟色胺（5-HT）转运体抑制剂，通常会降低对照动物的细胞外伏隔核（NAc）多巴胺（DA）水平，而不能作为强化剂。然而，值得注意的是，我们发现在慢性MPH治疗后，氟西汀具有精神兴奋剂药物的特征，表现出奖励作用和da升高作用。鉴于血清素能药物经常抑制DA激动剂的强化作用，这些和其他数据表明5-HT-DA相互作用可能发生根本性改变，即5-HT系统的激活导致边缘脑区域DA水平升高和奖励相关过程的激活。我们假设长期升高的DA水平导致VTA中的5-HT1B受体变得超敏感，它们的激活刺激DA释放到NAc和其他DA末端区域。我们假设这种变化可能会特别增加具有强5-羟色胺活性的药物（如MDMA）的强化作用，可能导致服用MPH的人滥用多种药物的风险增加。为了探索小鼠慢性MPH治疗对5-HT和DA系统之间特异性相互作用的影响，并探索大鼠MPH自我给药的神经化学和行为后果，我们建议研究1)小鼠i.p MPH治疗后5-HT的变化；2)小鼠双探针微透析时5-HT的作用位点；3)大鼠MPH自我给药4)MPH自我给药后5-HT的变化。

DESCRIPTION (provided by applicant): The clinical use of methylphenidate (MPH, Ritalin) for treatment of attention-deficit/hyperactivity disorder is widespread, and there is a growing problem of MPH abuse, especially in college-age adults. College students use MPH non-medically, mainly to enhance performance, stay up late to study or to get high. In addition, adults of all ages are using high doses of MPH off-label for energy and cognitive enhancement. The abused dosages of MPH are 2-10 times those recommended for clinical use, however, little is known about the neurobiological effects of chronic exposure to these MPH doses. Our laboratory has recently discovered an unexpected consequence of chronic high-dose MPH treatment in mice. We have found that the behavioral and neurochemical responses to fluoxetine are qualitatively transformed. Fluoxetine is a serotonin (5-HT) transporter inhibitor which normally reduces extracellular nucleus accumbens (NAc) dopamine (DA) levels in control animals and fails to act as a reinforcer. Remarkably, however, we found that following chronic MPH treatment, fluoxetine takes on the characteristics of a psychostimulant drug, exhibiting rewarding effects as well as DA-elevating effects. Given that serotonergic drugs often suppress the reinforcing effects of DA agonists, these and other data suggest the possibility of a fundamental alteration in 5-HT-DA interactions whereby activation of the 5-HT system leads to elevated DA levels in limbic brain areas and activation of reward-related processes. We hypothesize that chronically elevated DA levels causes 5-HT1B receptors in the VTA to become supersensitive and their activation stimulates DA release into the NAc and other DA terminal regions. We hypothesize that this change could specifically increase the reinforcing effects of drugs with strong 5-HT activity such as MDMA, potentially leading to enhanced risk of polydrug abuse in people taking MPH. To explore the impact of chronic MPH treatment in mice on specific interactions between the 5-HT and DA systems, and to explore the neurochemical and behavioral consequences of MPH self-administration in rats, we propose to examine 1) 5-HT alterations in response to i.p. MPH treatment in mice, 2) Sites of 5-HT action, using dual probe microdialysis in mice 3) MPH self-administration in rats 4) 5-HT alterations in response to MPH self-administration. PUBLIC HEALTH RELEVANCE: The prevalence of methylphenidate abuse has been estimated to be 5-26% of college students, and a significant proportion of these users develop problem use and dependence behaviors with other drugs. We have discovered an MPH-induced change in mice wherein 5-HT drugs (or doses) that were neutral or aversive became rewarding and elevated mesolimbic DA levels, and this has led us to postulate that abused drugs with strong 5-HT activity (such as MDMA, fenfluramine, methamphetamine, etc) may elicit greater euphoria/reward and thus have greater abuse/addiction potential in people who have taken MPH at high doses. Additionally, the MPH- induced changes in 5-HT receptors and function may lead to altered psychomotor effects and side effects of primarily 5-HT drugs such as antidepressants, which are commonly prescribed to adults who are exposed to MPH.