Asenapine alters the activity of monoaminergic systems following its subacute and long-term administration: An in vivo electrophysiological characterization

Asenapine is a tetracyclic atypical antipsychotic used for treatment of schizophrenia and mania. Previous in vivo electrophysiological studies demonstrated antagonistic action of asenapine at dopamine D2, serotonin (5-HT)2A, and α2-adrenergic receptors. Here, we assessed monoamine system activities after two-day and 21-day asenapine administration at a dosage (0.1 mg/kg/day) resulting in clinically relevant plasma levels. In the ventral tegmental area (VTA), asenapine increased the number of spontaneously active dopamine neurons, while firing parameters remained unchanged. Asenapine partially prevented the D2 autoreceptor-mediated inhibitory response to apomorphine after two days of administration. This effect was lost after 21 days of administration, suggesting adaptive changes leading to D2 receptor sensitization. Asenapine increased the firing activity of noradrenergic neurons in the locus coeruleus (LC) after 21, but not two days of administration. Furthermore, it potently blocked 5-HT2A receptors while α2-adrenergic receptors were unaffected by this drug regimen. Both acute and long-term asenapine administration partially blocked α2-adrenergic receptors in the CA3 region of the hippocampus, and noradrenergic tone on α1- and α2-adrenoceptors remained unchanged. In the dorsal raphe nucleus, asenapine increased the firing rate of 5-HT neurons after two, but not 21 days of administration. In addition, responsiveness of 5-HT1A autoreceptors was unaltered by asenapine. In the hippocampus, 21-day asenapine administration increased serotonergic tone by partial agonistic action on postsynaptic 5-HT1A and terminal 5-HT1B receptors. Taken together, asenapine had profound effects on both catecholamine systems, potently blocked 5-HT2A receptors, and enhanced 5-HT tone, effects that could be important in treatment of mood disorders and schizophrenia.