Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions

Major Depressive Disorder (MDD) is a serious neuropsychiatric disorder afflicting around 16–17 % of the global population and is accompanied by recurrent episodes of low mood, hopelessness and suicidal thoughts. Current pharmacological interventions take several weeks to even months for an improvement in depressive symptoms to emerge, with a significant percentage of individuals not responding to these medications at all, thus highlighting the need for rapid and effective next-generation treatments for MDD. Pre-clinical studies in animals have demonstrated that antagonists of the metabotropic glutamate receptor subtype 2/3 (mGlu_2/3 receptor) exert rapid antidepressant-like effects, comparable to the actions of ketamine. Therefore, it is possible that mGlu₂ or mGlu₃ receptors to have a regulatory role on the unique antidepressant properties of ketamine, or that convergent intracellular mechanisms exist between mGlu_2/3 receptor signaling and ketamine's effects. Here, we provide a comprehensive and critical evaluation of the literature on these convergent processes underlying the antidepressant action of mGlu_2/3 receptor inhibitors and ketamine. Importantly, combining sub-threshold doses of mGlu_2/3 receptor inhibitors with sub-antidepressant ketamine doses induce synergistic antidepressant-relevant behavioral effects. We review the evidence supporting these combinatorial effects since sub-effective dosages of mGlu_2/3 receptor antagonists and ketamine could reduce the risk for the emergence of significant adverse events compared with taking normal dosages. Overall, deconvolution of ketamine's pharmacological targets will give critical insights to influence the development of next-generation antidepressant treatments with rapid actions.