Dissociable Effects of 5-HT2C Receptor Antagonism and Genetic Inactivation on Perseverance and Learned Non-Reward in an Egocentric Spatial Reversal Task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT(2C) receptor (5-HT(2C)R) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT(2C)R on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT(2C)R antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT(2C)R KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. 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 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT(2C)R KO mice showed increased perseverance. 5-HT(2C)R KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT(2C)R function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT(2C)R antagonism and constitutive loss of the 5-HT(2C)R have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT(2C)R loss on the development and maintenance of cognitive function.