Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission

Mirtazapine (ORG 3770, Remeron(R)) is a new alpha(2)-adrenoceptor antagonis t which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine o n pre- and postsynaptic alpha(2)-adrenoceptors and to determine whether thi s drug could modulate serotonin (5-HT) neurotransmission. Acute administrat ion of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increa sed firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of alpha(2)-adrenergic autorecep tors of locus coeruleus neurons. Furthermore, acute mirtazapine injection t ransiently enhanced the firing activity of locus coeruleus NE neurons and a ttenuated the suppressant effect of the alpha(2)-adrenoceptor agonist cloni dine on these NE neurons. Sustained administration of mirtazapine for 21 da ys (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the fi ring rate of 5-HT neurons (75%) but a more modest increase in the firing ra te of NE neurons (30%), as well as to a desensitization of alpha(2)-adrener gic heteroreceptors on 5-HT terminals in the hippocampus. The desensitizati on of these heteroreceptors, resulting from an increased synaptic availabil ity of NE induced by mirtazapine would free 5-HT terminals from the inhibit ory influence of NE on 5-HT release. These modifications of 5-HT neurons le ad to an increased tonic activation of postsynaptic 5-HT1A receptors. The l atter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA, pyramidal neurons in mirtazapine-treated rats but not in controls. Thi s enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine. (C) 1998 Elsevier Science B.V. All rights reserved.