Dissociable Effects of Selective 5-HT2A and 5-HT2C Receptor Antagonists on Serial Spatial Reversal Learning in Rats

Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT2A antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT2C antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT2A and 5-HT2C receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT2C receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.