Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Psychotherapy, Carl Gustav Carus School of Medicine, TU Dresden, Dresden, Germany.
Department of Psychological and Brain Sciences, Department of Molecular, Cellular and Developmental Biology, The Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, USA.
Pharmacol Ther. 2021 Aug;224:107831. doi: 10.1016/j.pharmthera.2021.107831. Epub 2021 Mar 8.
Methamphetamine abuse leads to devastating consequences, including addiction, crime, and death. Despite decades of research, no medication has been approved by the U.S. Food and Drug Administration for the treatment of Methamphetamine Use Disorder. Thus, there is a need for new therapeutic approaches. Animal studies demonstrate that methamphetamine exposure dysregulates forebrain function involving the Group-I metabotropic glutamate receptor subtype 5 (mGlu), which is predominantly localized to postsynaptic sites. Allosteric modulators of mGlu offer a unique opportunity to modulate glutamatergic neurotransmission selectively, thereby potentially ameliorating methamphetamine-induced disruptions. Negative allosteric modulators of mGlu attenuate the effects of methamphetamine, including rewarding/reinforcing properties of the drug across animal models, and have shown promising effects in clinical trials for Anxiety Disorder and Major Depressive Disorder. Preclinical studies have also sparked great interest in mGlu positive allosteric modulators, which exhibit antipsychotic and anxiolytic properties, and facilitate extinction learning when access to methamphetamine is removed, possibly via the amelioration of methamphetamine-induced cognitive deficits. Clinical research is now needed to elucidate the mechanisms underlying the mGlu receptor-related effects of methamphetamine and the contributions of these effects to addictive behaviors. The growing array of mGlu allosteric modulators provides excellent tools for this purpose and may offer the prospect of developing tailored and effective medications for Methamphetamine Use Disorder.
甲基苯丙胺滥用会导致严重后果，包括成瘾、犯罪和死亡。尽管已经进行了几十年的研究，但美国食品和药物管理局尚未批准任何药物用于治疗甲基苯丙胺使用障碍。因此，需要新的治疗方法。动物研究表明，甲基苯丙胺暴露会使大脑前脑功能失调，涉及 I 型代谢型谷氨酸受体亚型 5（mGlu），mGlu 主要定位于突触后部位。mGlu 的变构调节剂为选择性调节谷氨酸能神经传递提供了独特的机会，从而有可能改善甲基苯丙胺引起的破坏。mGlu 的负变构调节剂可减弱甲基苯丙胺的作用，包括该药物在动物模型中的奖赏/强化特性，并且在焦虑症和重度抑郁症的临床试验中显示出有希望的效果。临床前研究也激发了对 mGlu 正变构调节剂的极大兴趣，mGlu 正变构调节剂具有抗精神病和抗焦虑特性，并在去除甲基苯丙胺时促进消退学习，可能通过改善甲基苯丙胺引起的认知缺陷。现在需要进行临床研究来阐明 mGlu 受体与甲基苯丙胺相关作用的机制以及这些作用对成瘾行为的贡献。越来越多的 mGlu 变构调节剂为此提供了极好的工具，并可能为开发针对甲基苯丙胺使用障碍的量身定制和有效的药物提供前景。
