mGluR5 antagonists for methamphetamine addiction

描述（由申请人提供）：甲基苯丙胺成瘾是日益严重的国家公共卫生问题，但迄今为止，还没有批准的药物治疗这种疾病。近年来，动物实验研究表明，5型代谢型谷氨酸受体（mGluR 5）参与实验成瘾的各个方面。例如，缺乏mGluR 5受体的小鼠不会自我施用可卡因，并且对其运动刺激作用漠不关心。类似地，选择性mGluR 5拮抗剂（也称为负变构调节剂）降低可卡因、海洛因、尼古丁和酒精在啮齿动物和/或非人灵长类动物中的强化作用。选择性mGluR 5拮抗剂也减少这些物种的复发样行为，目前正在I期和II期临床试验中进行测试，用于治疗其他医学疾病，包括抑郁症，焦虑症，偏头痛，胃食管反流病和脆性X综合征。到目前为止，这些化合物似乎被人类受试者良好耐受，没有严重的不良副作用。我们已经在大鼠中产生了令人鼓舞的初步数据，即选择性mGluR 5拮抗剂3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶（MTEP）剂量依赖性地减少了静脉内甲基苯丙胺自我给药、甲基苯丙胺在渐进比例强化时间表上的断点以及由药物相关线索和药物引发引起的甲基苯丙胺寻求行为的恢复。MTEP的这些作用不太可能是由于行为输出的一般性抑制，因为我们已经观察到MTEP不会改变食物自我管理，食物的渐进比例强化计划的断点，或线索诱导的觅食行为的恢复。这些数据支持我们的总体假设，即mGluR 5拮抗剂可能是用于治疗甲基苯丙胺成瘾的新型药理学药物。在本申请中，我们提出了额外的临床前药物开发研究，以进一步探索mGluR 5拮抗剂在治疗甲基苯丙胺成瘾中的潜在效用。具体而言，我们建议检查MTEP和临床验证的mGluR 5拮抗剂非诺班在甲基苯丙胺成瘾的啮齿动物模型中的作用，该模型更接近于人类甲基苯丙胺使用的模式（延长的每日自我给药和摄入量的狂欢式禁欲模式）。在具体目标1中，我们将检验以下假设：选择性mGluR 5拮抗剂将降低甲基苯丙胺的增强作用，随后由延长药物获取产生的摄入量增加。在具体目标2中，我们将检验以下假设：选择性mGluR 5拮抗剂将减弱在自我给药的狂欢-戒断模式后观察到的甲基苯丙胺增强功效的增加。总之，这些药物开发研究将为使用mGluR 5拮抗剂治疗人类甲基苯丙胺成瘾提供临床前基础。 公共卫生相关性：该提案的目的是为mGluR 5拮抗剂用于治疗甲基苯丙胺成瘾的潜在用途提供临床前基础。如果这些化合物最终被证明在治疗人类甲基苯丙胺成瘾方面有效，这将代表一项重大的公共卫生进步，并将大大降低这种疾病给社会带来的医疗、社会经济和法律的成本。

DESCRIPTION (provided by applicant): Methamphetamine addiction is growing national public health problem, yet to date there are no approved pharmacological treatments for this disorder. In recent years, animal studies have demonstrated that the type 5 metabotropic glutamate receptor (mGluR5) is involved in various aspects of experimental addiction. For example, mice lacking mGluR5 receptors do not self-administer cocaine and are indifferent to its locomotor stimulant effects. Similarly, selective mGluR5 antagonists (also known as negative allosteric modulators) reduce the reinforcing effects of cocaine, heroin, nicotine, and alcohol in rodents and/or non-human primates. Selective mGluR5 antagonists also reduce relapse-like behavior in these species, are currently being tested in Phase I and II clinical trials for the treatment of other medical conditions including depression, anxiety, migraine, gastroesophageal reflux disease, and Fragile X Syndrome. Thus far, these compounds appear to be well tolerated by human subjects with no serious adverse side effects. We have generated encouraging preliminary data in rats that the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) dose-dependently reduces intravenous methamphetamine self-administration, breakpoints for methamphetamine on a progressive ratio schedule of reinforcement, as well as reinstatement of methamphetamine-seeking behavior elicited by drug-associated cues and drug priming. These effects of MTEP are not likely due to a generalized inhibition of behavioral output, since we have observed that MTEP does not alter food self-administration, breakpoints for food on a progressive ratio schedule of reinforcement, or cue-induced reinstatement of food-seeking behavior. These data support our overall hypothesis that mGluR5 antagonists may be novel pharmacological agents for use in the treatment of methamphetamine addiction. In the present application, we propose additional preclinical medications development studies to further explore the potential utility of mGluR5 antagonists in the treatment of addiction to methamphetamine. Specifically, we propose to examine the effects of MTEP and the clinically validated mGluR5 antagonist fenobam in rodent models of methamphetamine addiction that more closely resemble patterns of human methamphetamine use (prolonged daily self-administration and binge-abstinent patterns of intake). In Specific Aim 1, we will test the hypothesis that selective mGluR5 antagonists will reduce the reinforcing effects of methamphetamine following escalation of intake produced by extended drug access. In Specific Aim 2, we will test the hypothesis that selective mGluR5 antagonists will attenuate the increases in the reinforcing efficacy of methamphetamine observed following binge-abstinent patterns of self-administration. Together, these medications development studies will provide a preclinical basis for the use of mGluR5 antagonists in the treatment of methamphetamine addiction in humans. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to provide a preclinical basis for the potential use of mGluR5 antagonists for the treatment of methamphetamine addiction. Should such compounds eventually prove to be effective in the treatment of methamphetamine addiction in humans, this would represent a major public health advancement and would significantly reduce the medical, socioeconomic and legal costs of this disorder to society.