Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain

Mirtazapine ([(+/-)-MIR], Remeron, ORG 3770) is an alpha-2 adrenoceptor antagonist endowed with antidepressant activity in humans. The aim of the present study was to assess the effects of (+/-)-MIR and of its (-)enantiomer [(-)-MIR] on pre- and postsynaptic alpha-2 adrenoceptors and to characterize their putative modulation of 5-HT neurotransmission. (+/-)-MIR (25 micrograms/kg i.v.) enhanced the effectiveness of the electrical stimulation of the ascending 5-HT pathway by blocking both alpha-2 adrenergic auto- and heteroreceptors. (-)-MIR (10 micrograms/kg i.v.) enhanced the effectiveness of these stimulations due to a selective action of (-)-MIR on the alpha-2 heteroreceptors located on 5-HT terminals. Both (+/-)- and (-)-MIR (500 micrograms/kg i.v.) blocked the suppressant effect of microiontophoretically applied norepinephrine (NE) on the firing activity of CA3 dorsal hippocampus pyramidal neurons, indicating their antagonistic effects on postsynaptic alpha-2 adrenoceptors. (+/-)-MIR (10- 250 micrograms/kg i.v.) enhanced dose-dependently the firing activity of the 5-HT neurons in naive rats, but not in 6-hydroxydopamine-pretreated rats. (+/-)-MIR also significantly increased the firing activity of locus ceruleus NE neurons. In contrast, (-)-MIR (10-250 micrograms/kg i.v.) failed to change the firing rate of dorsal raphe 5-HT neurons. In conclusion, these results suggest that both (+/-)-MIR and (-)-MIR are antagonists at postsynaptic alpha-2 adrenergic receptors, that (+/-)-MIR is an antagonist of somatodendritic as well as terminal alpha-2 adrenergic auto- and heteroreceptors, whereas (-)-MIR is a selective antagonist at alpha-2 adrenergic heteroreceptors. Furthermore, the inhibitory effect of (-)-MIR on locus ceruleus NE neurons appears to be mediated via 5-HT neurons because it is abolished by a 5,7-dihydroxytryptamine pretreatment.