Targeting mGlu 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 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.