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-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT( 2B), 5-HT(2C), 5-HT(5A), 5-HT(6) and 5-HT( 7). We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT(1A), 5-HT(2A) and 5-HT(2C). 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(1A) binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal CA(1) region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/kg) significantly decreased 5-HT(2A) 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-HT(2A) binding in the other brain regions studied. In contrast to the effects on 5-HT(1A) and 5-HT(2A) receptors, asenapine did not alter 5-HT(2C) binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine.