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

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.