Targeting mGlu5 for Methamphetamine Use Disorder

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 Meth amphetamine 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(5)), which is predominantly localized to postsynaptic sites. Allosteric modulators of mGlu(5) offer a unique opportunity to modulate glutamatergic neurotransmission selectively, thereby potentially ameliorating methamphetamine-induced disruptions. Negative allosteric modulators of mGlu5 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(5) 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(5) receptor-related effects of methamphetamine and the contributions of these effects to addictive behaviors. The growing array of mGlu5 allosteric modulators provides excellent tools for this purpose and may offer the prospect of developing tailored and effective medications for Methamphetamine Use Disorder. (C) 2021 Published by Elsevier Inc.

Automated summary

Research suggests that modulation of the mGlu(5) receptor with allosteric modulators may offer a promising approach for ameliorating the devastating consequences of methamphetamine abuse. Further clinical research is needed to understand the mechanisms underlying these effects and develop tailored medications for Methamphetamine Use Disorder.