Noradrenergic modulation of central serotonergic neurotransmission: Acute and long-term actions of mirtazapine

Mirtazapine (Org3770, Remeron) is a new alpha(2)-adrenoceptor antagonist which is an effective antidepressant drug. An in vivo electrophysiological paradigm in the rat was used to assess the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha(2)-adrenoceptors and to determine whether this drug can modulate serotonin (5-HT) neurotransmission. The acute administration of mirtazapine produced a rapid increase in both noradrenaline and 5-HT neurotransmission by blocking both alpha(2)-adrenergic auto- and heteroreceptors, resulting in an enhanced tonic activation of postsynaptic 5-HT receptors. Long-term administration showed that this tonic activation of postsynaptic 5-HT receptors was most likely enhanced after such a treatment as a result of a sustained increase in 5-HT neuronal activity in the presence of and due to inactivated alpha(2)-adrenergic heteroreceptors.