Pharmacological effects of milnacipran, a new antidepressant, given repeatedly on the alpha(1)-adrenergic and serotonergic 5-HT2A systems

Milanacipran (MIL) is a representative of a new class of antidepressants (S NRIs) which inhibit selectively the re uptake of serotonin and noradrenalin e but, in contrast to tricyclics, show no affinity for neurotransmitter rec eptors. The present study was aimed at determining whether repeated MIL tre atment induced adaptive changes in the alpha (1)-adrenergic and serotonergi c 5-HT2A systems, similar to those reported by us earlier for tricyclic ant idepressants. The experiments were carried out on male mice and rats. MIL w as 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 repea tedly potentiated the clonidine-induced aggressiveness and the methoxamine- induced exploratory hyperactivity, the effects mediated by alpha (1)-adreno ceptors. MIL did not change the number or affinity (B-max and K-D) of alpha (1)-adrenergic receptors in the cerebral cortex for [H-3]prazonsin, howeve r, the ability of the alpha (1)-adrenoceptor agonist phenylephrine to compe te for these sites was significantly enhanced. MIL given repeatedly (but no t acutely) inhibited both the head twitch reaction induced by L-5-HTP or (/-)DOI, the effects mediated by serotonergic 5-HT2A receptors. MIL also dec reased the binding (B-max) or [H-3]-ketanserin to 5-HT2A receptors in the c erebral cortex. The above results indicate that repeated MIL administration increases the responsiveness of alpha (1)-adrenergic system (behavioural a nd biochemical changes) and decreases the responsiveness of the serotonergi c 5-HT2A receptors (especially behavioural changes) as tricyclics do. It ma y 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.