mGluR5 antagonists for methamphetamine addiction

描述(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，但到目前为止，还没有批准的药物治疗这种疾病。近年来，动物研究表明，5型代谢型谷氨酸受体(MGluR5)参与了实验性成瘾的多个方面。例如，缺乏mGluR5受体的小鼠不会自我注射可卡因，对其运动刺激作用也无动于衷。同样，选择性mGluR5拮抗剂(也称为负变构调节剂)可减少可卡因、海洛因、尼古丁和酒精对啮齿动物和/或非人类灵长类动物的增强作用。选择性mGluR5拮抗剂还可以减少这些物种的复发行为，目前正在进行I期和II期临床试验，用于治疗其他疾病，包括抑郁、焦虑、偏头痛、胃食道反流病和脆性X综合征。到目前为止，这些化合物似乎很好地被人体耐受性，没有严重的副作用。我们在大鼠身上产生了令人鼓舞的初步数据，即选择性mGluR5拮抗剂3-[(2-methyl-1，3-thiazol-4-yl)ethynyl]pyridine(MTEP)以剂量依赖的方式减少静脉注射甲基苯丙胺的自我给药，减少甲基苯丙胺的断点，并恢复由药物相关线索和药物启动引起的甲基苯丙胺寻找行为。MTEP的这些影响不太可能是由于对行为输出的普遍抑制，因为我们观察到MTEP不会改变食物自我管理，不会改变食物在强化的累进比率时间表上的断点，也不会改变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mGluR5拮抗剂可能是用于治疗甲基苯丙胺成瘾的新型药理药物。在目前的应用中，我们建议进行更多的临床前药物开发研究，以进一步探索mGluR5拮抗剂在治疗甲基苯丙胺成瘾方面的潜在用途。具体地说，我们建议研究MTEP和临床验证的mGluR5拮抗剂非诺班在甲基苯丙胺成瘾啮齿动物模型中的作用，该模型更接近于人类甲基苯丙胺的使用模式(延长每日自我给药和暴饮暴食的模式)。在具体目标1中，我们将检验这样一种假设，即选择性mGluR5拮抗剂将减少甲基苯丙胺在延长药物接触所产生的摄入量增加后的增强作用。在具体目标2中，我们将测试选择性mGluR5拮抗剂将减弱甲基苯丙胺在自我给药狂欢-戒断模式下观察到的增强效果的假设。总之，这些药物开发研究将为使用mGluR5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：这项提案的目标是为mGluR5拮抗剂治疗甲基苯丙胺成瘾的潜在使用提供临床前基础。如果这些化合物最终被证明对治疗人类的甲基苯丙胺成瘾有效，这将是公共卫生的重大进步，并将显著降低这种疾病给社会带来的医疗、社会经济和法律成本。

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.