Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances.

Abstract 5-HT 4 and 5-HT 6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT 4 receptors (5-HT 4 R) or blockade of 5-HT 6 receptors (5-HT 6 R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer’s disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT 4 R or 5-HT 6 R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT 4 R partial agonist (RS-67333) or a 5-HT 6 R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT 4 R activation and 5-HT 6 R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits.