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The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice

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Abstract

Rationale

Inhibition of the glycine transporter 1 (GlyT1) activity increases extra-cellular glycine availability in the CNS. At glutamatergic synapses, increased binding to the glycine-B site located in the N-methyl-d-aspartate receptor (NMDAR) can enhance neurotransmission via NMDARs. Systemic treatment of 2-chloro-N-[(S)-phenyl [(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734), a selective GlyT1 inhibitor, is effective against social recognition impairment induced by neonatal phencyclidine treatment and enhances pre-pulse inhibition in a mouse strain (DBA/2) with intrinsic sensorimotor gating deficiency, suggesting that SSR504734 may be an effective cognitive enhancer.

Objective

The objective of the study was to examine if SSR504734 exhibits a promnesic effect on working memory function in wild-type C57BL/6 mice using an automatic continuous alternation task.

Materials and methods

Hungry mice were trained to alternate their nose pokes between two food magazines across successive discrete trials in an operant chamber in order to obtain food reward. Correct choice on a given trial thus followed a non-matching or win-shift rule in relation to the preceding trial, with manipulation of the demand on memory retention, by varying the delay between successive trials.

Results

Pre-treatment with SSR504734 (30 mg/kg, i.p.) improved choice accuracy when the delay from the previous trial was extended to 12–16 s. Furthermore, a dose–response analysis (3, 10, 30 mg/kg) revealed a clear dose-dependent efficacy of the drug: 3 mg/kg was without effect, whilst 10 mg/kg led to an intermediate enhancement in performance.

Conclusion

The present findings represent the first demonstration of the promnesic effects of SSR504734 under normal physiological conditions, lending further support to the suggestion of its potential as a cognitive enhancer.

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Acknowledgements

The present study was supported by the Swiss Federal Institute of Technology (ETH) Zurich and the NCCR Neural Plasticity & Repair (funded by the Swiss National Science Foundation). The authors are also grateful to Dr. Bernard Scatton (Sanofi-Aventis, Paris, France) for his support for the present study and in providing the compound SSR504734. The authors also thank Peter Schmid for his excellent technical support, and the animal husbandry staff at the Laboratory of Behavioural Neurobiology, for their maintenance of the subjects used in the experiments.

Disclosure

The experimental manipulations and procedures described here had been previously approved by the Swiss Cantonal Veterinary Office and conform to the ethical standards required by the Swiss Act and Ordinance on Animal Protection and the European Council Directives 86/609/EEC. No conflicts of interest are to be declared by any of the authors of the present article.

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  1. Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology, Schorenstrasse 16, 8603, Schwerzenbach, Switzerland

    Philipp Singer, Joram Feldon & Benjamin K. Yee

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Singer, P., Feldon, J. & Yee, B.K. The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice. Psychopharmacology 202, 371–384 (2009). https://doi.org/10.1007/s00213-008-1286-5

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