On-line microdialysis studies in freely moving rats showed mirtazapine (2 mg/kg s.c.) to increase hippocampal 5-HT (5-hydroxytryptamine) and dihydroxyphenyl acetic acid (DOPAC)--a measure of noradrenergic activity--by approximately 80%. The increase in DOPAC is probably caused by blockade of alpha 2A-autoreceptors on noradrenergic terminals. Indirect alpha 1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory alpha 2A-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.
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.