Electrophysiological characterization of the effects of asenapine at 5-HT1A, 5-HT2A, α2-adrenergic and D2 receptors in the rat brain

Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT1A), ventral tegmental area D2, locus coeruleus 5-HT2A, and α2-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at α2-adrenoceptors (ED50, 85 ± 2 µg/kg), 5-HT2A (ED50, 75 ± 2 µg/kg) and D2 receptors (ED50, 40 ± 2 µg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT1A receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT1A antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT2A, D2, α2-adrenergic receptors and provide evidence to support its 5-HT1A partial agonistic activity.