Pharmacological effects of milnacipran, a new antidepressant, given repeatedly on the alpha1-adrenergic and serotonergic 5-HT2A systems.

Milanacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the reuptake of serotonin and noradrenaline but, in contrast to tricyclics, show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated MIL treatment induced adaptive changes in the alpha1-adrenergic and serotonergic 5-HT2A systems, similar to those reported by us earlier for tricyclic antidepressants. The experiments were carried out on male mice and rats. MIL was administered at a dose of 10 or 30 mg/kg p.o. once or repeatedly (twice daily for 14 days). The obtained results showed that MIL administered repeatedly potentiated the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, the effects mediated by alpha1-adrenoceptors. MIL did not change the number or affinity (Bmax and K(D)) of alpha1-adrenergic receptors in the cerebral cortex for [3H]prazonsin, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for these sites was significantly enhanced. MIL given repeatedly (but not acutely) inhibited both the head twitch reaction induced by L-5-HTP or (+/-)DOI, the effects mediated by serotonergic 5-HT2A receptors. MIL also decreased the binding (Bmax) or [3H]-ketanserin to 5-HT2A receptors in the cerebral cortex. The above results indicate that repeated MIL administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes) and decreases the responsiveness of the serotonergic 5-HT2A receptors (especially behavioural changes) as tricyclics do. It may be concluded that the lack of MIL affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment with antidepressants.