MGlu2/3 Receptor Antagonists as Rapid-Acting Antidepressants

Abstract

Since the discovery of the robust and rapid-acting antidepressant effects of ketamine in patients with treatment-resistant depression, the glutamatergic system has gained significant attention as an attractive target for the development of novel antidepressants. As part of the glutamatergic system, metabotropic glutamate (mGlu) receptors are of interest because mGlu receptors play regulatory roles in glutamate transmission. Accumulating evidence has suggested that a blockade of group II mGlu receptors, consisting of mGlu2 and mGlu3 receptors, is an effective approach to exert antidepressant actions. Indeed, animal studies using selective mGlu2/3 receptor antagonists have revealed that mGlu2/3 receptor antagonists have antidepressant profiles similar to those of ketamine: rapid-acting antidepressant effects and efficacy in models refractory to current medications. Moreover, mGlu2/3 receptor antagonists do not show ketamine-like side effects such as psychotomimetic-like behaviors and abuse potential. Therefore, mGlu2/3 receptor antagonists can function as novel antidepressants that may be devoid of ketamine-like side effects.