Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission1These results have been reported in part in two publications (Haddjeri et al. 1996, 1997).1

May 20, 1999Journal of affective disorders

Short- and long-term effects of the antidepressant mirtazapine on brain serotonin signaling

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Abstract

Sustained administration of mirtazapine for 21 days resulted in a 75% increase in the firing rate of serotonin neurons.

Acute mirtazapine administration temporarily increased the firing activity of serotonin neurons in the dorsal raphe.
This increase was linked to the activation of serotonin neurons by norepinephrine, which was blocked in norepinephrine-lesioned rats.
Long-term treatment also caused a 30% increase in the firing rate of norepinephrine neurons.
Desensitization of alpha 2-adrenergic receptors on serotonin terminals in the hippocampus was observed after prolonged mirtazapine use.
These changes may enhance serotonin release by reducing norepinephrine's inhibitory influence, leading to increased activation of serotonin receptors.

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Mirtazapine (ORG 3770, Remeron) is a new alpha 2-adrenoceptor antagonist 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 on pre- and postsynaptic alpha 2-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration 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 increased 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 autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of alpha 2-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3 pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine.

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Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission1These results have been reported in part in two publications (Haddjeri et al. 1996, 1997).1

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