title: Time-dependent impact of glutamatergic modulators on the promnesiant effect of 5-HT6R blockade on mice recognition memory.
abstract: Selective antagonists at serotonin 5-HT6receptors (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.
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France. Electronic address: rachel.asselot@unicaen.fr.
authors.forename: Rachel
authors.initials: R
authors.lastname: Asselot
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Simon-O'Brien
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebourgeois
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Nee
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Virgile
authors.initials: V
authors.lastname: Delaunay
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Duchatelle
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Bouet
authors.affiliation: Normandie Univ, UNICAEN,GMPc, 14000 Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Dauphin
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010875:Pipecolic Acids / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D010875:Pipecolic Acids; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D018698:Glutamic Acid; C053672:selfotel; C117443:SB 271046
keywords: CGS 19755 (PubChem CID: 68736); Mice; NFPS (PubChem CID: 5311283); Recognition memory; SB-271046 (PubChem CID: 5312149); Serotonin type 6 receptor