Effect of repeated treatment with mirtazapine on the central alpha1-adrenergic receptors.

Mirtazapine (MIR) is an antidepressant which enhances noradrenergic and serotonergic 5-HT 1A neurotransmission via antagomism of central α 2 -adrenergic autoreceptors and heteroreceptors. The drugs does not inhibit noradrenaline and serotonin reuptake but blocks the 5-HT 2 and 5-HT 3 receptors and has high affinity only for central and peripheral histamine H 1 receptors. The present study was aimed at determining whether repeated MIR treatment induced adaptive changes in the α 1 -adrenergic receptors, similar to those reported by us early for tricyclic antidepressants, The experiments were carried out on male mice and rats. MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days). The obtained results showed that MIR administrated repeatedly potentiated the methoxamine- induced exploratory hyperactivity in rats and clonidineinduced aggressiveness in mice, those effects being mediated by α 1 -adrenergic receptors. MIR given repeatedly (but not acutely) increased the binding (B max ) of [ 3 H]prazosin to α 1 -adrenergic receptors in cerebral cortex, however, the ability of the α 1 -adrenoceptor agonist phenylephrine to compete for the these sites was not significantly changed. The above results indicate that repeated MIR administration increases the responsiveness of α 1 -adrenergic system (behavioural and biochemical changes), as tricyclics do. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.