Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions

The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR and western blotting. Acute administration of mirtazapine did not affect extracellular serotonin level in raphe nuclei or cortex; however, chronic administration increased extracellular serotonin level in raphe nuclei without affecting that in cortex. Blockade of 5-HT1A receptor, but not that of the 5-HT2A/2C receptor, enhanced the effects of acute administration of mirtazapine on extracellular serotonin level in raphe nuclei. Chronic mirtazapine administration reduced the inhibitory function associated with somatodendritic 5-HT1A receptor in raphe nuclei, but enhanced postsynaptic 5-HT1A receptor in serotonergic innervated cortical regions. Chronic administration reduced the expression of mRNA and protein of serotonin transporter and 5-HT1A receptor in raphe nuclei, but not in the cortices. These results suggested that acute administration of mirtazapine probably activated serotonergic transmission, but its stimulatory action was abolished by activated inhibitory 5-HT1A receptor. Chronic administration of mirtazapine resulted in increased extracellular serotonin level via reduction of serotonin transporter with reduction of somatodendritic 5-HT1A autoreceptor function in raphe nuclei. These pharmacological actions of mirtazapine include its serotonergic profiles as noradrenergic and specific serotonergic antidepressant (NaSSA).

Research highlights
► Acute mirtazapine does not affect extracellular serotonin level in raphe nuclei.
► Chronic mirtazapine increased extracellular serotonin level in raphe nuclei.
► Chronic mirtazapine reduced the somatodendritic 5-HT1A receptor in raphe nuclei.
► Chronic mirtazapine enhanced postsynaptic 5-HT1A receptor in cortex.
► Chronic mirtazapine educed the expression of serotonin transporter and 5-HT1A receptor.