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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-HT 2A antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT 2C 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-HT 2A and 5-HT 2C receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT 2C 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.

We have recently demonstrated that systemic administration of 5-HT(2C) and 5-HT(2A) receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT(2C) and 5-HT(2A) receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT(2C) and 5-HT(2A) receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT(2C) and 5-HT(2A) receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT(2C) receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 microg) and perseverative errors to criterion (0.3 and 1.0 microg) compared with controls. However, the highest dose (1.0 microg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT(2C) receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT(2C) receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.

Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.

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