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Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

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Abstract

Rationale

Several agents that stimulate the glycine site of N-methyl-d-aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed.

Objectives

We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and d-serine, and a partial agonist, d-cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site.

Results

High doses of glycine (1.6 g/kg) and d-serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, d-cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and l-serine levels, but decreased d-serine levels in the prefrontal cortex.

Conclusions

The findings of the present study suggest that glycine and d-serine but not d-cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.

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Acknowledgment

We thank Meiji Pharmaceutical for providing 2 g of d-cycloserine. Funding for this study was partly provided by a grant from the Minister of Education, Culture, Sports, Science, and Technology of Japan (to E.S. and K.H.).

Conflict of interest statement

The authors declare no conflict of interest except for 2 g of d-cycloserine transferred from Meiji Pharmaceutical.

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Authors and Affiliations

  1. Department of Integrative Neurophysiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan

    Eiji Shimizu, Mami Kohno & Daisuke Matsuzawa

  2. Department of Psychiatry, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan

    Nobuhisa Kanahara, Shintaro Ohgake, Tasuku Hashimoto, Yukihiko Shirayama & Masaomi Iyo

  3. Division of Clinical Neuroscience, Center of Forensic Mental Health, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan

    Yuko Fujita & Kenji Hashimoto

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  1. Nobuhisa Kanahara
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  2. Eiji Shimizu
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  3. Shintaro Ohgake
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  4. Yuko Fujita
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  10. Masaomi Iyo
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Correspondence to Eiji Shimizu.

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Kanahara, N., Shimizu, E., Ohgake, S. et al. Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801. Psychopharmacology 198, 363–374 (2008). https://doi.org/10.1007/s00213-008-1151-6

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  • DOI: https://doi.org/10.1007/s00213-008-1151-6

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