mGlu2/3 receptor as a novel target for rapid acting antidepressants

Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.