The Glutamate mGluR5 Receptor as a Pharmacological Target to Enhance Cognitive Function: Emerging Evidence from Psychosis Models

Abstract

Schizophrenia is a profoundly disabling condition affecting approximately 1% of the population. Although often defined by the presence of so-called ‘positive’ symptoms of hallucinations and delusions, sufferers are typically more affected by the more insidious cognitive and ‘negative’ (social withdrawal and amotivational) symptoms. The dopaminergic hypothesis has been a dominant neurobiological model, particularly as the majority of current antipsychotic medications act upon dopamine pathways, but it is notably incomplete; noteworthy, existing medications have, at best, very limited effects upon cognitive deficits. The glutamatergic (Glu) system has attracted attention in recent times as a putative target, though modulation of this ubiquitous system in the brain is not without danger; to this end the metabotropic mGluR5 receptor has emerged as a possible mechanism through which safe Glu modification might be effected. Most data at this time have emerged from animal model studies; these are interesting, with positive results, but need replication in human samples. At present, the future use of mGluR5 modifying drugs has yet to be established.