Abstract
Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain.
Highlights
Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and exerts its effects through the activation of several receptor subtypes
The antipsychotic potential of mGluR5 positive modulators may arise from a modulatory effect on the mesolimbic dopaminergic pathway, as suggested by the decrease in basal dopamine levels in the nucleus accumbens induced by ADX47273 [105]
Blockade of mGluR5 has been shown to be devoid of effect on foodmotivated instrumental behaviour and cue-induced reinstatement of food-seeking [152,155]. These findings suggest that selective blockade of mGluR5 might represent an interesting mechanism for the treatment of addictive behaviours to various drug classes
Summary
Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and exerts its effects through the activation of several receptor subtypes. The antipsychotic potential of mGluR5 positive modulators may arise from a modulatory effect on the mesolimbic dopaminergic pathway, as suggested by the decrease in basal dopamine levels in the nucleus accumbens induced by ADX47273 [105]. A modulatory role of mGluR5s on cognitive function is indicated by the finding that CDPPB, another selective mGluR5 positive allosteric modulator, reduces the characteristic set-shifting impairment induced by NMDA receptor blockade in rats [106].
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