Methylphenidate, Serotonin and Dopamine Interactions

哌醋甲酯、血清素和多巴胺的相互作用

• 批准号: 8287148
• 负责人: SARA RAULERSON JONES
• 金额: $ 27.78万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287148
• 关键词: Adult; Adverse effects; Age; Antidepressive Agents; Area; Attention deficit hyperactivity disorder; Autoreceptors; Behavior; Behavioral; Brain; Characteristics; Chronic; Clinical; Cocaine; Control Animal; Corpus striatum structure; Data; Dependence; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Euphoria; Exhibits; Exposure to; Fenfluramine; Fluoxetine; Human; Label; Laboratories; Lead; Ligands; Location; Measures; Mediator of activation protein; Methamphetamine; Methylphenidate; Microdialysis; Mus; Neurobiology; Nucleus Accumbens; Performance; Pharmaceutical Preparations; Prevalence; Procedures; Process; Property; Psychological reinforcement; Rattus; Rewards; Risk; Ritalin; Schedule; Self Administration; Serotonin; Serotonin Agents; Serotonin Receptor 5-HT1B; Site; Study Section; System; Testing; Time; Ventral Tegmental Area; addiction; cognitive enhancement; college; dopamine system; dosage; drug of abuse; ecstasy; extracellular; inhibitor/antagonist; methylphenidate abuse; multidrug abuse; neurochemistry; psychostimulant; public health relevance; raphe nuclei; receptor; receptor binding; receptor function; reinforcer; response; university student

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.

描述（由申请人提供）：哌醋甲酯（MPH，Ritalin）用于治疗注意力缺陷/多动症障碍的临床使用普遍存在，并且越来越多的MPH滥用问题，尤其是在大学年龄成年人中。大学生非医疗使用MPH，主要是为了提高表现，熬夜学习或变得高高。此外，所有年龄段的成年人都使用高剂量的MPH非标签外能量和认知增强。 MPH的滥用剂量是建议临床使用的2-10倍，但是，对于长期暴露于这些MPH剂量的神经生物学作用知之甚少。我们的实验室最近发现了小鼠慢性高剂量MPH治疗的意外结果。我们发现，对氟西汀的行为和神经化学反应是定性转化的。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中伏伏核（NAC）多巴胺（DA）水平，并且无法充当增强剂。但是，值得注意的是，我们发现，经过长期的MPH治疗后，氟西汀采用了精神刺激药物的特征，表现出有益的效果以及DA-DE升高作用。鉴于血清素能药物经常抑制DA激动剂的增强作用，这些数据和其他数据表明，5-HT-DA相互作用的基本改变可能会导致5-HT系统的激活导致边缘大脑区域的DA水平升高以及与奖励相关过程的激活。我们假设长期升高的DA水平会导致VTA中的5-HT1B受体变得超敏感，并且它们的激活刺激DA释放到NAC和其他DA末端区域。我们假设这种变化可以特别增加具有强大5-HT活性的药物的增强作用，例如MDMA，这可能会导致服用MPH的人滥用多药的风险。为了探索慢性MPH治疗在小鼠中对5-HT和DA系统之间特定相互作用的影响，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）1）响应于i.p.的5-HT改变。在小鼠中使用MPH治疗2）5-HT作用的位点，使用小鼠中的双探针微透析3）大鼠中的MPH自我给药4）响应MPH自我给药时5-HT改变。 公共卫生相关性：据估计，甲基苯甲酸酯滥用的患病率占大学生的5-26％，其中很大一部分用户与其他药物一起发展了问题的使用和依赖行为。我们已经发现了小鼠的MPH诱导的变化，其中5-HT药物（或剂量）具有中性或厌恶的性变化，并升高了中脂比的DA水平，这使我们假设我们假设滥用5-HT活性的药物（例如MDMA，MDMA，Fenfluramine，Fenfluramine，甲基苯丙胺等）可能会增加甲基氨基异化的效果，从而使MID-FENMAILIA均具有更大的责任。高剂量。此外，MPH诱导的5-HT受体和功能的变化可能会导致精神运动的影响改变和主要是5-HT药物的副作用，例如抗抑郁药，这些药物通常是针对暴露于MPH的成年人的。