Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Studies have recently suggested that blockade of 5-HT6 receptors (5-HT6R) improves memory processes. As episodic memory alteration is one of the first deficits observed during normal aging and in neurological and neuropsychiatric disorders ( Alzheimer's disease, schizophrenia), the present study sought to characterize the effects of 5-HT6R blockade on spatial recognition memory, which can be considered as 'episodic-like' memory, in rodents. We quantified the effects of the selective 5-HT6R antagonist SB-271046 (10 mg/kg, i.p.), using the two-trial place recognition task in the Y-maze, on acquisition, consolidation, and retrieval of spatial recognition memory in young adult mice (6-week-old; intertrial intervals (ITIs) 30, 60, 120, 240, and 360 min) and on the consolidation of spatial recognition memory in aged mice (3-, 12-, 18-, and 21-month-old; ITI 60 and 240 min). SB-271046-treated young adult mice explored the new arm more after a 240-min (pre-acquisition) and 360-min (post-acquisition) ITI, whereas vehicle-treated animals failed to discriminate the new arm when the ITI exceeded 120 min ( pre-acquisition) or 240 min (post-acquisition). Aged mice, which expressed spatial memory deficits, explored the new arm more after a 60-min ITI (21-month-old) and a 240-min ITI ( 18- and 21-month-old) when treated with SB-271046. Consequently, 5-HT6R blockade improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory. This study provides further support for the use of 5-HT6R antagonists in the treatment of episodic memory disorders related to aging as well as neurological disorders such as Alzheimer's disease and schizophrenia.