Pharmacological effects of milnacipran, a new antidepressant, given repeatedly on the α₁-adrenergic and serotonergic 5-HT_2A systems

Summary.

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 α₁-adrenergic and serotonergic 5-HT_2A 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 α₁-adrenoceptors. MIL did not change the number or affinity (B_max and K_D) of α₁-adrenergic receptors in the cerebral cortex for [³H]prazonsin, however, the ability of the α₁-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-HT_2A receptors. MIL also decreased the binding (B_max) or [³H]-ketanserin to 5-HT_2A receptors in the cerebral cortex. The above results indicate that repeated MIL administration increases the responsiveness of α₁-adrenergic system (behavioural and biochemical changes) and decreases the responsiveness of the serotonergic 5-HT_2A 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.