Time-dependent impact of glutamatergic modulators on the promnesiant effect of 5-HT6R blockade on mice recognition memory

Selective antagonists at serotonin 5-HT6 receptors (5-HT6R) improve memory performance in rodents and are currently under clinical investigations. If blockade of 5-HT6R is known to increase glutamate release, only two studies have so far demonstrated an interaction between 5-HT6R and glutamate transmission, but both, using the non-competitive NMDA antagonist MK-801, insensitive to variations of glutamate concentrations. In a place recognition task, we investigated here in mice the role of glutamate transmission in the beneficial effects of 5-HT6R blockade (SB-271046). Through the use of increasing intervals (2, 4 and 6h) between acquisition and retrieval, we investigated the time-dependent impact of two different glutamatergic modulators. NMDAR-dependant glutamate transmission (NMDA Receptors) was either blocked by the competitive antagonist at NMDAR, CGS 19755, or potentiated by the glycine transporter type 1 (GlyT1) inhibitor, NFPS. Results showed that neither SB-271046, nor CGS 19755, nor NFPS, alter behavioural performances after short intervals, i.e. when control mice displayed significant memory performances (2h and 4h) (respectively 10, 3, and 0.625mg.kg−1). Conversely, with the 6h-interval, a situation in which spontaneous forgetting is observed in control mice, SB-271046 improved recognition memory performances. This beneficial effect was prevented when co-administered with either CGS 19755 or NFPS, which themselves had no effect. Interestingly, a dose-dependent effect was observed with NFPS, with promnesic effect observed at lower dose (0.156mg.kg−1) when administrated alone, whereas it did no modify promnesic effect of SB-271046. These results demonstrate that promnesiant effect induced by 5-HT6R blockade is sensitive to the competitive blockade of NMDAR and underline the need of a fine adjustment of the inhibition of GlyT1. Overall, our findings support the idea of a complex crosstalk between serotonergic and glutamatergic systems in the promnesic properties of 5-HT6R antagonists.