Involvement of serotonergic system in the effect of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test

Abstract

The blockade of metabotropic glutamate 5 (mGlu5) receptor has been reported to exert antidepressant effects in several animal models. We previously reported that both ketamine and an mGlu5 receptor antagonist exerted an effect in a novelty-suppressed feeding (NSF) test, and that the effect of ketamine may be mediated through an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-dependent increase in serotonergic transmission. However, the involvement of the serotonergic system in the effect of mGlu5 receptor antagonists in the NSF test is not well understood. Therefore, we examined the roles of the serotonergic system in the effect of an mGlu5 receptor antagonist, 6-methyl-2-(phenylethynyl)pyridine hydrochloride (MPEP), in the NSF test in mice. The administration of MPEP significantly shortened the latency to feed, which was not attenuated by the AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). The effect of MPEP was abolished by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effect of MPEP was blocked by a serotonin (5-HT)2A/2C receptor antagonist, ritanserin, but not by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635). These results suggest that the effect of an mGlu5 receptor antagonist may be mediated by the serotonergic system, including the stimulation of the 5-HT2A/2C receptor, in an AMPA receptor-independent manner in the NSF test.

Potential of Glutamate-Based Drug Discovery for Next Generation Antidepressants

“…[ 70 ]). In addition, the antidepressant effect of MTEP was blocked by pretreatment with an inhibitor of 5-HT synthesis [ 71 ], which was confirmed by our recent report that the effect of MPEP is blocked by an inhibitor of 5-HT synthesis in the NSFT [ 72 ]. Thus, similar to ketamine and mGlu2/3 receptor antagonists, serotonergic transmission may be involved in the actions of mGlu5 receptor antagonists as well.…”

“…Thus, similar to ketamine and mGlu2/3 receptor antagonists, serotonergic transmission may be involved in the actions of mGlu5 receptor antagonists as well. In contrast, the effects of mGlu5 receptor antagonists were blocked by a 5-HT 2A/2C receptor antagonist, but not by a 5-HT 1A receptor antagonist, when evaluated using the TST [ 71 ] and the NSFT [ 72 ], and these effects are different from those produced by the mechanisms of ketamine and mGlu2/3 receptor antagonists. Recently, the mGlu5 receptor antagonist Basimglurant was administered as an adjunctive treatment to ongoing SSRI or SNRI treatment in a randomized, double-blind, placebo-controlled study, and an antidepressant effect was observed in patients with MDD, although the effect did not reach statistical significance when assessed using MADRS as a primary endpoint [ 73 ].…”

Vulnerability to depressive behavior induced by overexpression of striatal Shati/Nat8l via the serotonergic neuronal pathway in mice

“…There are some reports that in the prefrontal cortex, the group II mGluR2/3 antagonist is associated with the serotonergic neuronal system in depression-like behaviors [18][19][20]. However, functional effect of the dorsal striatum on depression-like behaviors is still unknown.…”

Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy

“…Although mGlu5 signaling does influence mTOR signaling (46), mTOR activation does not seem to be involved in the rapid antidepressant effects induced by the mGlu5 NAM MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) or its close structural analogue MPEP (2-methyl-6-(phenylethynyl)pyridine) (47, 48). Further, while mGlu5 activation can lead to an internalization of AMPA receptors (49), the antidepressant action of mGlu5 antagonism does not seem be prevented by AMPA receptor antagonists (50, 51), in contrast to what was reported for ketamine (52).…”