Methylphenidate, Serotonin and Dopamine Interactions

描述（由申请人提供）：临床上广泛使用哌甲酯（MPH，利他林）治疗注意力缺陷/多动障碍，MPH滥用问题日益严重，尤其是在大学年龄的成年人中。大学生使用MPH非医学，主要是为了提高成绩，熬夜学习或获得高。此外，所有年龄段的成年人都在使用高剂量的MPH来提高能量和认知能力。MPH的滥用剂量是临床推荐剂量的2-10倍，然而，人们对慢性暴露于这些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中发现了慢性高剂量MPH治疗的意外后果。我们发现，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）转运蛋白抑制剂，通常会降低对照动物的细胞外核多巴胺（NAc）水平，但不能起到抑制剂的作用。然而，值得注意的是，我们发现在慢性MPH治疗后，氟西汀呈现出精神兴奋剂药物的特征，表现出奖励作用以及DA升高作用。考虑到多巴胺能药物经常抑制DA激动剂的增强作用，这些和其他数据表明5-HT-DA相互作用的根本改变的可能性，从而5-HT系统的激活导致边缘脑区DA水平升高和奖励相关过程的激活。我们推测，长期升高的DA水平导致5-HT 1B受体在腹侧被盖区变得超敏感，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-HT活性的药物（如MDMA）的增强作用，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，我们建议检查1）小鼠对腹膜内MPH治疗的5-HT改变，2）5-HT作用的位点，用双探针微透析法测定小鼠的MPH浓度; 3）MPH自身给药大鼠的MPH浓度; 4）MPH自身给药后5-HT的变化。 公共卫生相关性：据估计，哌甲酯滥用的流行率为5-26%的大学生，这些用户中有很大一部分发展出使用其他药物的问题和依赖行为。我们在小鼠中发现了MPH诱导的变化，其中中性或厌恶的5-HT药物（或剂量）变得有益并升高了中边缘DA水平，这使我们假设滥用具有强5-HT活性的药物（例如摇头丸、芬氟拉明、甲基苯丙胺等）可能会引起更大的欣快感/奖励，从而在服用高剂量MPH的人中具有更大的滥用/成瘾潜力。此外，MPH诱导的5-HT受体和功能的变化可能导致主要5-HT药物如抗抑郁药的精神作用和副作用的改变，这些药物通常开给暴露于MPH的成年人。

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.