Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Blockade of alpha(2) adrenoceptors and histamine H-1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine. However, it remains unclear how mirtazapine's actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei. Using dual-probe microdialysis, we determined the roles of alpha(2) and H-1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices. Mirtazapine (< 30 mu M) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H-1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H-1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H-1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN alpha(2) adrenoceptor blockade was attenuated by concurrent DRN H-1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN alpha(2) adrenoceptor inhibition was unaffected by concurrent MRN H-1 receptor blockade. These results suggest that enhanced serotonergic transmission resulting from alpha(2) adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H-1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.