Metabotropic glutamate receptor targets for neuropsychiatric disorders

The actions of glutamate in the synapse are modulated by metabotropic glutamate (mGlu) receptors (mGlu1-8) that are expressed on nerve terminals, post-synaptic sites and glia. Recently, new positive and negative orthosteric or allosteric modulators for mGlu receptor groups or subtypes have been discovered allowing for pharmacological studies in animal models and early clinical investigations. Evidence indicates that mGlu2/3 receptor agonists and mGlu5 receptor antagonists may be useful to treat anxiety and drug abuse disorders, whereas mGlu2/3 agonists have activity in certain psychosis models. Interestingly, potentiators of mGlu5 receptors might enhance cognition or treat negative symptoms in schizophrenia, whereas antagonists for mGlu2/3 receptors have activity in models of depression. Comparatively, less is known about the potential role of modulating other mGlu receptors (mGlu1, 4, 7, and 8) in psychiatric disorders; however, progress has been made with less selective agents and transgenic animal tools, suggesting that other novel approaches are on the horizon.

Section editors:David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USAC. Anthony Altar – Psychiatric Genomics, Gaithersburg, USATheresa Branchek – Lundbeck Research, Paramus, USA