Blockade of glycine transporter 1 by SSR-504734 promotes cognitive flexibility in glycine/NMDA receptor-dependent manner

Accumulating evidence suggests that cognitive processes may be regulated by glycine concentration in the local environment of glutamate N-methyl-d-aspartate receptor (NMDAR). The concentration of glycine is controlled, among other factors, by the glycine transporter 1 (GlyT1). While GlyT1 inhibitors are developed for a number of indications including cognitive improvement, little is known about their effects in tasks depending on prefrontal cortical function. We examined the effect of GlyT1 inhibitor SSR-504734 on cognitive flexibility assessed in the attentional set-shifting task in rats (ASST). The second goal was to elucidate whether SSR-504734 effect has been due to the compound’s action at glycine/NMDAR site. Rats treated with SSR-504734 (3 and 10 mg/kg, IP) required significantly less trials to criteria during extra-dimensional shift (EDs) phase of the ASST. The effect of SSR-504734 (3 mg/kg) was completely prevented by the glycine/NMDAR site antagonist, L-687,414 (30 mg/kg, IP) that by itself exerted no effect on cognitive flexibility. Present study demonstrates that the elevation of glycine concentration through the blockade of its reuptake facilitates cognitive flexibility. As this effect was fully blocked by glycine/NMDAR antagonist, SSR-504734-induced cognitive improvement is likely mediated through glycine action at NMDAR. It is suggested that GlyT1 inhibitors like SSR-504734 may represent a useful pharmacological approach for cognitive enhancement, especially in domains critically affected in schizophrenia.

► GlyT1 inhibitor SSR-504734 facilitated cognitive flexibility in rats.
► This effect was fully blocked by the glycine/NMDAR antagonist L-687,414.
► The SSR-504734-induced cognitive enhancement is mediated by glycine/NMDAR.