On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039

Abstract

RationaleSeveral studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear.ObjectivesThe aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated.ResultsThe results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound.ConclusionsThe results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.

The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN

“…To verify this hypothesis, we first investigated the involvement of the AMPA receptor in the mPFC in the antidepressant effects of the mGlu2/3 receptor antagonist and ketamine. We confirmed that the antidepressant effects of LY341495 and ketamine were abolished by pretreatment with systemic administration of an AMPA receptor antagonist, NBQX, in the present condition as previously reported (Koike et al, 2011a, b;Maeng et al, 2008;Pałucha-Poniewiera et al, 2010). Moreover, the antidepressant effects of LY341495 and ketamine were also blocked by microinjection of NBQX into the mPFC.…”

“…Of note, we have confirmed previously that the present treatment condition is sufficient for the pharmacological depletion of 5-HT in mice (Fukumoto et al, 2014). Contrary to our findings, it has been reported that the acute antidepressant effects of ketamine and an mGlu2/3 receptor antagonist in the FST and tail suspension test, respectively, were independent of the 5-HTergic systems (Gigliucci et al, 2013; Role of 5-HT in an mGlu2/3 antagonist and ketamine K Fukumoto et al Pałucha-Poniewiera et al, 2010). Although these differences may be ascribed to differences in the study paradigms or conditions among the studies, the precise reason remains unclear at present.…”

“…We have demonstrated the antidepressant effects of mGlu2/3 receptor antagonists in several animal models of depression (Chaki et al, 2004;Karasawa et al, 2005;Pałucha-Poniewiera et al, 2010), including a model that is depression refractory to current medications (Koike et al, 2013a). In addition, we and others have found evidence to suggest that mGlu2/3 receptor antagonists share some of the neural and synaptic mechanisms underlying their antidepressant effects with ketamine, such as AMPA receptor stimulation and subsequent activation of the TrkB receptor and mTOR signalings, that increase the levels of synaptic proteins in the prefrontal cortex (PFC) (Dwyer et al, 2012; Koike et al, 2011a; Koike et al, 2013b;Pałucha-Poniewiera et al, 2010). Therefore, like ketamine, mGlu2/3 receptor antagonists may have the potential to exert the rapid and sustained antidepressant effects and, indeed, an mGlu2/3 receptor antagonist has been shown to exert the rapid and sustained antidepressant effects in the chronic unpredictable stress model (Dwyer et al, 2013).…”

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

“…Previous studies demonstrate that mGlu2/3 antagonists, notably MGS0039 and LY341,495, have antidepressant actions in standard behavioural models [54,55]. In addition, the antidepressant actions of mGlu2/3 antagonists are blocked by pretreatment with an AMPA receptor antagonist, similar to the blockade of ketamine [54,56].…”

Depression Viewed as a GABA/Glutamate Imbalance in the Central Nervous System

“…The involvement of other than mGlu 2/3 receptor subtypes in the action of LY341495 cannot be ruled out, either as the compound is a mixed antagonist of both group II and group III receptors. The mechanism of the antidepressantlike action of both compounds was shown to be independent on the serotonergic system; the drugs were still active after the depletion of serotonin, and their action was not antagonized by serotonergic receptor antagonists ritanserin or WAY100635 (Pałucha-Poniewiera et al, 2010b). However, the activity of the compounds was antagonized by NBQX, further supporting the role of the AMPA receptor in the antidepressant action of mGlu 2/3 receptor ligands Karasawa et al, 2006;Kawashima et al, 2005;PaluchaPoniewiera et al, 2010b).…”