Insight into the function of Group I and Group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders

Abstract

Following the molecular cloning in the early 1990s of the metabotropic glutamate receptors (mGlu1-8), research that focused on the physiology, pharmacology and function of these receptors revealed their potential role in CNS disorders. Numerous psychiatric and neurological dis-orders are indeed linked to changes in excitatory processes, in which glutamate plays a key role. In contrast to ligand-gated ion channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and kainate], which are responsible for fast excitatory transmission, mGlu receptors have a more modulatory role, by contributing to fine-tuning of synaptic efficacy, and control of the accuracy and sharpness of the transmission. Given the fact that the mGlu receptors are G-protein coupled, they obviously constitute new 'drugable' targets for the treatment of various CNS disorders. Due to the recent emergence of subtype-specific ligands for Group I and II mGlu receptors, this review will concentrate on the molecular characteristics, brain localization, pharmacology and physiological role of these receptors, in order to provide further insights into their therapeutic potential.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

“…It is a heteroceptor modulating serotonin and dopamine transmission and associated effects. 301,303,304 Type II metabotropic glutamate receptor agonists (GRM2 and 3) block the behavioural and cognitive effects of NMDAR antagonism. 305 The peptide neurotransmitter N-acetylaspartylglutamate (NAAG; which is hydrolysed to produce NAA and glutamate), is itself a GRM3 agonist and has NMDAR activity.…”

Glutamate as a therapeutic target in psychiatric disorders

“…Group I receptors are positively linked to phospholipase C, whereas both group II and III receptors are negatively linked to adenyl cyclase. 43 As a result, group I receptors function predominantly to potentiate both presynaptic glutamate release and postsynaptic NMDA neurotransmission, 44 with mGLUR5 receptors showing significant colocalization with NMDA receptors in rodents. 45 In contrast, group II and III receptors, in general, serve to limit glutamate release, particularly during conditions of glutamate spillover from the synaptic cleft.…”

Neuroimaging - Clinical Applications

“…Some of these compounds or their derivatives are amenable to radiolabeling with fluorine-18 or carbon-11. For example, a series of potent 2-fluoro-3-pyridyl-triazol derivatives such as FTIDC (10) and FPTQ (11) MGluR1 expression is localized throughout the nervous system (Layton, 2005;Spooren et al, 2003). The distribution of mGluR1 in the peripheral nervous system (Bhave et al, 2001;Lesage, 2004;Skerry & Genever, 2001) and in the CNS has been studied using various methods including radioligand autoradiography and immunohistochemical techniques (Lavreysen et al, 2003;Lavreysen et al, 2004a;Shigemoto & Mizuno., 2000;Simonyi et al, 2005).…”