Asenapine induces differential regional effects on serotonin receptor subtypes

Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7. We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT1A, 5-HT2A and 5-HT2C. Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA(1) and CA(3) regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT(1)A binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal C-A1 region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/ kg) significantly decreased 5-HT2A binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT2A binding in the other brain regions studied. In contrast to the effects on 5-HT1A and 5-HT2A receptors, asenapine did not alter 5-HT2C binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT1A and 5-HT2A receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine.