Enhancement of Spatial Reversal Learning by 5-HT2C Receptor Antagonism Is Neuroanatomically Specific

We have recently demonstrated that systemic administration of 5-HT2C and 5-HT2A receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT2C and 5-HT2A receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT2C and 5-HT2A 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-HT2C and 5-HT2A receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT2C 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 mu g) and perseverative errors to criterion (0.3 and 1.0 mu g) compared with controls. However, the highest dose (1.0 mu g) 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-HT2C receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT2C receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.