AMPA Receptor–mTOR Activation is Required for the Antidepressant-Like Effects of Sarcosine during the Forced Swim Test in Rats: Insertion of AMPA Receptor may Play a Role

Abstract

Sarcosine, an endogenous amino acid, is a competitive inhibitor of the type I glycine transporter and an N-methyl-d-aspartate receptor (NMDAR) coagonist. Recently, we found that sarcosine, an NMDAR enhancer, can improve depression-related behaviors in rodents and humans. This result differs from previous studies, which have reported antidepressant effects of NMDAR antagonists. The mechanisms underlying the therapeutic response of sarcosine remain unknown. This study examines the role of mammalian target of rapamycin (mTOR) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) activation, which are involved in the antidepressant-like effects of several glutamatergic system modulators. The effects of sarcosine in a forced swim test (FST) and the expression levels of phosphorylated mTOR signaling proteins were examined in the absence or presence of mTOR and AMPAR inhibitors. In addition, the influence of sarcosine on AMPAR trafficking was determined by analyzing the phosphorylation of AMPAR subunit GluR1 at the PKA site (often considered an indicator for GluR1 membrane insertion in neurons). A single injection of sarcosine exhibited antidepressant-like effects in rats in the FST and rapidly activated the mTOR signaling pathway, which were significantly blocked by mTOR inhibitor rapamycin or the AMPAR inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) pretreatment. Moreover, NBQX pretreatment eliminated the ability of sarcosine to stimulate the phosphorylated mTOR signaling proteins. Furthermore, GluR1 phosphorylation at its PKA site was significantly increased after an acute in vivo sarcosine treatment. The results demonstrated that sarcosine exerts antidepressant-like effects by enhancing AMPAR–mTOR signaling pathway activity and facilitating AMPAR membrane insertion.HighlightsA single injection of sarcosine rapidly exerted antidepressant-like effects with a concomitant increase in the activation of the mammalian target of rapamycin mTOR signaling pathway.The antidepressant-like effects of sarcosine occur through the activated AMPAR–mTOR signaling pathway.Sarcosine could enhance AMPAR membrane insertion via an AMPAR throughput.

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice

“…A recent study further confirmed that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine is essential for its antidepressant effects and the antidepressant actions of ketamine metabolites are independent of NMDAR inhibition but involve sustained activation of AMPARs (Zanos et al, 2016). Similarly, the antidepressant-like effect of sarcosine has been revealed through the activated AMPAR-mTOR signaling pathway (Chen et al, 2015). It still remains to be determined whether DMG also produced antidepressant-like effect through this pathway and how much involvement of its metabolite sarcosine.…”

Modulation of the activity of <em>N</em>-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

“…In rodent models, chronic sarcosine treatment significantly ameliorates the increased immobility induced by chronic unpredictable stress in the forced swim test (FST), a classical behavioral paradigm for measuring antidepressant action 46. In support of these findings, a single injection of sarcosine rapidly activates the mTOR signaling pathway, an effect abolished by rapamycin or AMPAR blockade, indicating that sarcosine exerts antidepressant-like effects by enhancing AMPAR-mTOR signaling pathway activity and by facilitating AMPAR membrane insertion 47. Rapastinel (formerly GLYX-13) is a novel synthetic compound that modulates the NMDAR in a glycine-like fashion when examined pharmacologically and electrophysiologically 48.…”

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

“…Among them, GLYX-13 has been proved to have sustained effects. On the other hand, D-serine (Malkesman et al 2012) and glycine transporter-I inhibitor sarcosine (Chen et al 2015;Huang et al 2013), which are assumed to potentiate NMDAR function through glycine site, can also improve depression-like behaviors in rodent models and in human depression (Huang et al 2013). Modulation of NMDAR glycine site might be majorly contributed to the rapid and sustained antidepressant-like effect of betaine, although betaine elevated 5-HT levels and has been suggested to be like a traditional antidepressant (Kim et al 2013).…”