Methylphenidate, Serotonin and Dopamine Interactions

哌醋甲酯、血清素和多巴胺的相互作用

• 批准号: 8142214
• 负责人: SARA RAULERSON JONES
• 金额: $ 27.26万
• 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/8142214
• 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，利他林）用于治疗注意力缺陷/多动症的临床应用非常广泛，并且 MPH 滥用问题日益严重，尤其是在大学生中。大学生使用 MPH 非医学用途，主要是为了提高表现、熬夜学习或获得快感。此外，所有年龄段的成年人都在标签外使用高剂量的 MPH 来增强能量和认知能力。 MPH 的滥用剂量是临床推荐剂量的 2-10 倍，然而，人们对长期暴露于这些 MPH 剂量的神经生物学影响知之甚少。我们的实验室最近发现了对小鼠进行长期高剂量 MPH 治疗的意外后果。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。氟西汀是一种血清素 (5-HT) 转运蛋白抑制剂，通常会降低对照动物的细胞外伏隔核 (NAc) 多巴胺 (DA) 水平，并且不能起到强化剂的作用。然而值得注意的是，我们发现长期 MPH 治疗后，氟西汀呈现出精神兴奋药物的特征，表现出奖励作用以及 DA 升高作用。鉴于血清素药物经常抑制 DA 激动剂的增强作用，这些数据和其他数据表明 5-HT-DA 相互作用可能发生根本改变，从而激活 5-HT 系统导致边缘脑区域 DA 水平升高并激活与奖励相关的流程。我们假设，长期升高的 DA 水平会导致 VTA 中的 5-HT1B 受体变得超级敏感，并且它们的激活会刺激 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（例如 MDMA）的增强作用，从而可能导致服用 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 系统之间特定相互作用的影响，并探索大鼠自我给药 MPH 的神经化学和行为后果，我们建议检查 1) 5-HT 反应的改变至IP小鼠中的 MPH 治疗，2) 5-HT 作用位点，在小鼠中使用双探针微透析，3) 大鼠中的 MPH 自我给药，4) MPH 自我给药反应中的 5-HT 变化。 公共卫生相关性：据估计，大学生中哌醋甲酯滥用的比例为 5-26%，其中很大一部分使用者出现了使用其他药物的问题和依赖行为。我们发现了 MPH 诱导的小鼠变化，其中中性或厌恶的 5-HT 药物（或剂量）变得有益，并且中脑边缘 DA 水平升高，这使我们假设滥用具有强 5-HT 活性的药物（例如因为 MDMA、芬氟拉明、甲基苯丙胺等）可能会引起更大的欣快感/奖励，因此对于服用高剂量 MPH 的人来说，滥用/成瘾的可能性更大。此外，MPH 引起的 5-HT 受体和功能的变化可能会导致主要 5-HT 药物（例如抗抑郁药）的精神运动效应和副作用发生改变，这些药物通常用于接触 MPH 的成年人。