Group II
metabotropic glutamate receptor (
mGluR2/3) agonists once showed promise as non-dopaminergic
antipsychotic drugs because of their efficacy in alleviating symptoms of
schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in
mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether
mGluR2/3 is still a promising therapeutic target for
schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of
mGluR2/3 agonists, especially on
mGluR2/3 agonists' mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of
mGluR2/3 agonists, the distinct roles between
mGluR2 and
mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with
mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of
mGluR2/3 as a therapeutic target for
schizophrenia. This review will thus shed light on the comprehensive features of the translational potential
mGluR2/3 agonists as well as the need for further research into the more selective activation of
mGluR2.