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 D-2, serotonin (5-HT)(2A), and alpha(2)-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 D-2 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 D-2 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 alpha(2)-adrenergic receptors were unaffected by this drug regimen. Both acute and long-term asenapine administration partially blocked alpha(2)-adrenergic receptors in the CA3 region of the hippocampus, and noradrenergic tone on alpha(1)- and alpha(2)-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. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.