Reversal learning deficits are a feature of many human psychopathologies and their associated animal models and have recently been shown to involve the 5-HT_2C receptor (5-HT_2CR). Successful reversal learning can be reduced to two dissociable cognitive mechanisms, to dissipate associations of previous positive (opposed by perseverance) and negative (opposed by learned non-reward) valence.

This study aims to explore the effect of reducing activity at the 5-HT_2CR on the cognitive mechanisms underlying spatial reversal learning in the mouse.

Experiment 1 used the 5-HT_2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design, experiment 2 used 5-HT_2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two lit nosepoke holes. This was followed by three conditions; (1) full reversal, where contingencies reversed; (2) perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS−.

SB242084 treated and 5-HT_2CR KO mice showed enhanced reversal learning seen as a decrease in trials, correct responses, and omissions to criterion in the full reversal condition. Similar effects were observed in the learned non-reward condition but SB242084 treated and 5-HT_2CR KO mice did not differ from controls in the perseverance condition. SB242084 treated, but not 5-HT_2CR KO mice, showed decreases in all latency indices in every condition.

Reducing activity at the 5-HT_2CR facilitates reversal learning in the mouse by reducing the influence of previously non-rewarded associations.