Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway

Abstract

Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…The present observations provide a framework to examine other agents, including novel glycine site agonists, like Rapastinel [93] and NSX-2925 [14], the uptake inhibitors TASP0315003 [88] and bitopertin [35,36], D-amino acid oxidases inhibitors like sodium benzoate [22,106], and inhibitors of kynurenine aminotransferase II all of which modify PFC glutamatergic signalling [107,108]. Furthermore, it would be interesting to study agents acting at the neuronal alanine-serinecysteine-1 transporter which is implicated in the control of extracellular D-serine and glycine [8,109].…”

D-Serine: A Cross Species Review of Safety

“…Antipsychotics likely cause EPS via dopamine type 2 receptor blockade in the striatum. In a pre-clinical mouse study (129), both D-serine (300 mg/kg) and sodium benzoate (600 mg/kg) administered intraperitoneally attenuated haloperidol induced bradykinesia. D-serine showed a U-shaped curve for attenuation, as no effects were seen for 100 or 1,000 mg/kg doses.…”

The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review

“…Consistent with this notion, brain ageing is associated with the reduced NMDA receptor function, in turn leading to declined memory and learning performance [78]. Stimulation of glycine binding to NMDA receptors have been shown to ameliorate extrapyramidal symptoms of neuromuscular function [79] and a study has shown that glycine administration could improve extrapyramidal and cognitive symptoms in Schizophrenic patients [54]. NMDA receptors have also been implicated in other age-related diseases such as diabetes [80] and hypertension [81].…”