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Int. J. Mol. Sci. 2017, 18(7), 1416; doi:10.3390/ijms18071416

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

Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
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Received: 1 June 2017 / Revised: 23 June 2017 / Accepted: 29 June 2017 / Published: 3 July 2017
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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. View Full-Text
Keywords: antipsychotics; d-cycloserine; extrapyramidal side effects; glycine-binding site agonists of NMDA receptors; nigrostriatal dopaminergic system; schizophrenia antipsychotics; d-cycloserine; extrapyramidal side effects; glycine-binding site agonists of NMDA receptors; nigrostriatal dopaminergic system; schizophrenia
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MDPI and ACS Style

Shimizu, S.; Sogabe, S.; Yanagisako, R.; Inada, A.; Yamanaka, M.; Iha, H.A.; Ohno, Y. Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway. Int. J. Mol. Sci. 2017, 18, 1416.

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