mGlu Receptor Modulation in Murine Models of Stress and Affective Disorders

Abstract

Mood and anxiety disorders account for approximately 10% of the global disease burden, and currently available treatments are not satisfactory. Novel antidepressant and anxiolytic approaches with reduced side effects, increased compliance, and rapid onset must be developed to improve outcomes for broad patient populations. The recent clinical approval of esketamine for major depressive disorder has revitalized research into novel mechanism-based treatments, particularly those that directly engage the glutamate system. Several lines of evidence from patients and postmortem samples now implicate metabotropic glutamate (mGlu) receptors in the etiology of affective disorders. In this chapter, we review the clinical research studies and drug treatment trials related to mGlu receptor modulation for affective disorders. Genome-wide association studies have repeatedly linked the genes encoding mGlu5 receptors and other mGlu receptor subtypes with depression, yet clinical trials using mGlu receptor allosteric modulators have not reached efficacy on their primary endpoints. Nonetheless, high placebo rates and mixed results underscore strong motivation to continue investigating the mechanisms of action of mGlu receptor modulators. This chapter provides detailed and practical methodological descriptions of rodent models of mood and anxiety disorders, describing several assays to test how mGlu receptor modulation regulates phenotypes related to stress, anxiety, and affect. Continued preclinical research will improve our basic understanding of affective disorders and should inform patient selection procedures incorporated in clinical trial design.