Methylphenidate, Serotonin and Dopamine Interactions

描述(申请人提供)：临床上广泛使用哌醋甲酯(mph，利他林)治疗注意力缺陷/多动障碍，滥用mph的问题日益严重，尤其是在大学年龄的成年人中。大学生使用mph非医学用途，主要是为了提高成绩，熬夜学习或兴奋。此外，所有年龄段的成年人都在使用标签外的大剂量MPH来增强能量和认知能力。滥用的mph剂量是推荐临床使用剂量的2-10倍，然而，人们对长期接触这些mph剂量的神经生物学影响知之甚少。我们的实验室最近在小鼠身上发现了一个意想不到的后果，那就是长期高剂量的MPH治疗。我们发现，氟西汀的行为和神经化学反应发生了质的变化。氟西汀是一种5-羟色胺(5-羟色胺)转运体抑制剂，正常情况下会降低对照动物的细胞外伏隔核(NAC)多巴胺(DA)水平，而不起到增强剂的作用。然而，值得注意的是，我们发现，在慢性MPH治疗之后，氟西汀呈现出精神刺激药物的特征，表现出奖励效应和DA升高效应。鉴于5-羟色胺能药物经常抑制DA激动剂的增强效应，这些和其他数据表明，5-羟色胺-DA相互作用可能发生根本改变，从而激活5-羟色胺系统导致边缘脑区DA水平升高，并激活与奖励相关的过程。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终末区域。我们假设，这一变化可能会特别增加MDMA等具有较强5-羟色胺活性的药物的强化作用，潜在地导致服用MPH的人滥用多药的风险增加。为了探讨慢性MPH治疗对5-羟色胺和多巴胺系统之间特异性相互作用的影响，以及MPH自身给药对大鼠神经化学和行为的影响，我们提出了1)5-羟色胺对腹腔注射的影响。2)5-羟色胺的作用部位，在小鼠中使用双探针微透析；3)大鼠MPH自身给药；4)5-羟色胺对MPH自身给药反应的改变。 公共卫生相关性：据估计，大学生滥用哌醋甲酯的流行率为5%-26%，其中很大一部分吸毒者出现了问题使用和对其他药物的依赖行为。我们在小鼠身上发现了一种由PMH引起的变化，其中中性或厌恶的5-羟色胺药物(或剂量)变得有回报，并提高了中脑边缘DA水平，这使我们假设滥用具有强烈5-羟色胺活性的药物(如MDMA、芬氟拉明、甲基苯丙胺等)可能会引起更大的欣快感/奖赏，从而在高剂量服用MPH的人中有更大的滥用/成瘾潜力。此外，MPH引起的5-羟色胺受体和功能的改变可能会导致精神运动效应的改变，以及主要是5-羟色胺药物的副作用，如抗抑郁药，这些药物通常是给接触MPH的成年人开的。

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.