REVIEW The possible involvement of metabotropic glutamate receptors in schizophrenia Amir Krivoy a, ⁎ , Tsvi Fischel a,b , Abraham Weizman a,b,c a Geha Mental Health Center, Petach-Tikva, Israel b Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel c Felsenstein Medical Research Center, Campus Bailinson, Tel-Aviv University, Petach-Tikva, Israel Received 10 July 2007; received in revised form 16 September 2007; accepted 7 November 2007 Abstract Glutamate disruption is thought to have a major role in schizophrenia brain processes, possibly involving NMDA hypofunction. The metabotropic glutamate receptors are distributed in brain regions related to schizophrenia and seem to affect glutamate release in a moderate way. Compounds modulating these receptors are being investigated in animal models of schizo- phrenia, in an attempt to discover new antipsychotics. This article reviews the current research data regarding the role of these receptors in schizophrenia animal models. It was found that more research was done on Group I and II metabotropic receptors while investigation of group III receptors is still trailing behind. Accumulating evidence shows that mGluR5 antagonists by themselves do not necessarily disrupt pre-pulse inhibition (PPI), but can exacerbate disruption of PPI caused by MK-801 and PCP, while positive modulation of this receptor has beneficial effects on these models of psychosis. Group II agonists are also showing beneficial effects in animal models. It seems that metabotropic glutamate receptor modulators could be developed into a novel treatment of schizophrenia by altering glutamate release, thus overcoming the putative NMDA hypofunction. Although the implications from these pre-clinical studies to human schizophrenia patients are premature, the data obtained with some compounds point to promising results for drug development. More studies, with agents active at other mGluRs in animal models and schizophrenia patients as well as with human subjects are needed in order to clarify the role of the metabotropic glutamate receptors in the pathophysiology and pharmacotherapy of schizophrenia. © 2007 Elsevier B.V. and ECNP. All rights reserved. KEYWORDS Schizophrenia; Glutamate; Metabotropic receptors; NMDA; mGluRs ⁎ Corresponding author. E-mail address: krivoy@zahav.net.il (A. Krivoy). 0924-977X/$ - see front matter © 2007 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2007.11.001 www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2008) 18, 395–405