Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials

Abstract

BackgroundSarcosine, a glycine transporter type 1 inhibitor and an N-methyl-D-aspartate (NMDA) receptor co-agonist at the glycine binding site, potentiates NMDA receptor function. Structurally similar to sarcosine, N,N-dimethylglycine (DMG) is also N-methyl glycine-derivative amino acid and commonly used as a dietary supplement. The present study compared the effects of sarcosine and DMG on NMDA receptor-mediated excitatory field potentials (EFPs) in mouse medial prefrontal cortex brain slices using a multi-electrode array system.ResultsGlycine, sarcosine and DMG alone did not alter the NMDA receptor-mediated EFPs, but in combination with glutamate, glycine and its N-methyl derivatives significantly increased the frequency and amplitude of EFPs. The enhancing effects of glycine analogs in combination with glutamate on EFPs were remarkably reduced by the glycine binding site antagonist 7-chlorokynurenate (7-CK). However, DMG, but not sarcosine, reduced the frequency and amplitude of EFPs elicited by co-application of glutamate plus glycine. D-cycloserine, a partial agonist at the glycine binding site on NMDA receptors, affected EFPs in a similar manner to DMG. Furthermore, DMG, but not sarcosine, reduced the frequencies and amplitudes of EFPs elicited by glutamate plus D-serine, another endogenous ligand for glycine binding site.ConclusionsThese findings suggest that sarcosine acts as a full agonist, yet DMG is a partial agonist at glycine binding site of NMDA receptors. The molecular docking analysis indicated that the interactions of glycine, sarcosine, and DMG to NMDA receptors are highly similar, supporting that the glycine binding site of NMDA receptors is a critical target site for sarcosine and DMG.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0314-8) contains supplementary material, which is available to authorized users.

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms

“…DMG is a partial agonist at the glycine binding site of NMDA receptors. However, although DMG alone did not alter the NMDA receptor-mediated excitatory field potentials, DMG acts as an agonist at the glycine binding site of NMDA receptors in combination with glutamate [ 62 ]. Therefore, the agonist effect of DMG on NMDAR can be decreased with decreased medial prefrontal glutamate–glutamine concentration, and decreased NMDAR expression has been reported to occur during chronic administration of oxytocin [ 10 ].…”

“…As demonstrated in our previous study [ 11 ], the behavioral effects of oxytocin can be observed at a maximum of 2 weeks, with deterioration at 4 weeks, in a 6-week treatment period. Taken together, these findings suggest that in the acute phase (e.g., 0–2 weeks), increases in DMG induced with oxytocin administration can act as a partial agonist at the glycine binding site of NMDAR with glutamate [ 62 ]. In addition, administered oxytocin has clinical effects during the acute phase.…”

N-Alkyl-α-amino acids in Nature and their biocatalytic preparation

“…Sarcosine (1), currently used as a dietary supplement and as a non-specific glycine transport inhibitor, also holds promise as an adjuvant therapy with sodium benzoate for the treatment of schizophrenia (Lin et al, 2017) and depression, as recently discussed in a review (Mathew, 2013). N, , which is also used as a dietary supplement, reportedly improves immune responses, acts as an athletic performance enhancer, displays anticonvulsant activity and may have use as an antidepressant in patients with autism (Lee et al, 2017). According to a recent review by Wilcken, glycine betaine (3) is used pharmaceutically in anhydrous form as Cystadane®, an adjunctive treatment for homocystinuria and can offer numerous other benefits to human health such as attenuation of liver injury (Wilcken, 2017).…”

Adjunctive Sarcosine and N-Acetylcysteine Use for Treatment-Resistant Schizophrenia

“…In the glutamate hypothesis of schizophrenia, abnormal glutamate uptake by glial cells can result in decreased N-methyl-D-aspartate (NMDA) receptor function [1,[3][4][5][6][7]. Dysfunction of NMDA receptors results in the disruption of downstream dopamine signaling.…”

“…Modulation of the NMDA receptor via allosteric binding of glycine can enhance glutamate binding [1,[3][4]. Sarcosine (N-methyl glycine) is a type 1 glycine transporter inhibitor (GlyT1), that increases the synaptic concentration of glycine by preventing its reuptake by glial cells.…”