Repeated 5-HT6 receptor activation facilitates flexible behavior in C57BL/6J mice

The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.