Therapeutic potential and underlying mechanism of sarcosine (N-methylglycine) in N-methyl-D-aspartate (NMDA) receptor hypofunction models of schizophrenia

Abstract

Background: Compelling animal and clinical studies support the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia and suggest promising pharmacological agents to ameliorate negative and cognitive symptoms of schizophrenia, including sarcosine, a glycine transporter-1 inhibitor. Aims and methods: It is imperative to evaluate the therapeutic potential of sarcosine in animal models, which provide indispensable tools for testing drug effects in detail and elucidating the underlying mechanisms. In this study, a series of seven experiments was conducted to investigate the effect of sarcosine in ameliorating behavioral deficits and the underlying mechanism in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase-null mutant (SR−/−) mice) NMDAR hypofunction models. Results: In Experiment 1, the acute administration of 500/1000 mg/kg sarcosine (i.p.) had no adverse effects on motor function and serum biochemical responses. In Experiments 2–4, sarcosine significantly alleviated MK-801-induced (0.2 mg/kg) brain abnormalities and behavioral deficits in MK-801-induced and SR−/− mouse models. In Experiment 5, the injection of sarcosine enhanced CSF levels of glycine and serine in rat brain. In Experiments 6–7, we show for the first time that sarcosine facilitated NMDAR-mediated hippocampal field excitatory postsynaptic potentials and influenced the movement of surface NMDARs at extrasynaptic sites. Conclusions: Sarcosine effectively regulated the surface trafficking of NMDARs, NMDAR-evoked electrophysiological activity, brain glycine levels and MK-801-induced abnormalities in the brain, which contributed to the amelioration of behavioral deficits in mouse models of NMDAR hypofunction.

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

“…However, the subanalgesic doses of each inhibitor failed to produce significant increase in glycine content in the CSF, but a tendency of this increase was noticed. Data on increase in the glycine level in CSF upon treatments of rodents with selective GlyT-1 or GlyT-2 inhibitors have been published by other research groups [28][29][30]. However, to the best of our knowledge, there are no data available on the effects of the GlyT-1 and GlyT-2 inhibitors' combination on the pain evoked by nerve damage or on the glycine level in the CSF.…”

Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia

“…Alternatively, although recent studies report that SR and DAO are not solely expressed in astrocytes [100][101][102], astrocytes play a vital role in the secretion of D-serine and the regulation of NMDAR function [96,103]. Several animal studies with constitutive deletion of SR in SR -/mutant mice indicated that these mice had long-term D-serine deficiency, neurobiological abnormalities, spatial and fear memory deficits, sociality problems, and hyperlocomotion activity [104][105][106][107][108]. Intriguingly, a recent study further indicated that SR -/mutant mice exhibited a reduction in the freezing response in the trace fear conditioning task and hyperlocomotion in the open-field task, which were normalized by a single administration of sarcosine (an astrocytic glycine transporter-1 inhibitor) [108].…”

“…Several animal studies with constitutive deletion of SR in SR -/mutant mice indicated that these mice had long-term D-serine deficiency, neurobiological abnormalities, spatial and fear memory deficits, sociality problems, and hyperlocomotion activity [104][105][106][107][108]. Intriguingly, a recent study further indicated that SR -/mutant mice exhibited a reduction in the freezing response in the trace fear conditioning task and hyperlocomotion in the open-field task, which were normalized by a single administration of sarcosine (an astrocytic glycine transporter-1 inhibitor) [108]. However, little is known about NMDAR hypofunction induced by DAO overexpression in animal models.…”

“…First, analysis of electrophysiological endophenotypes of NMDAR-mediated transmission is a widely used method for understanding pathological neuronal networks and tripartite synaptic signal integrations [139,140]. For example, sarcosine, an astrocytic glycine transporter-1 inhibitor, enhanced NMDARmediated field excitatory postsynaptic potentials and bound to the GMS of NMDARs in the CA1 region of mouse hippocampal slices [108]. Both in vitro electrophysiological studies [29,141,142] and in vivo experiments [29,143,144] with cell type-specific recordings were proven to be useful in revealing that astrocytes mediate neuronal transmission and oscillation.…”

“…Both in vitro electrophysiological studies [29,141,142] and in vivo experiments [29,143,144] with cell type-specific recordings were proven to be useful in revealing that astrocytes mediate neuronal transmission and oscillation. Second, molecular imaging with positron emission tomography (PET) provides the quantification of diverse physiological, biochemical, and functional processes in schizophrenic patients and animal models [108,[145][146][147][148]. Intriguingly, the most commonly used PET radiotracer, 18 F-FDG, is driven by astrocytic glutamate transport [149].…”