Mirtazapine is an atypical antidepressant employed clinically for the treatment of major
depression. As a multipotent antagonist it acts at α2a-adrenergic receptors (α2a -ARs).
serotonin type-2A receptors (5-HT2a-Rs) and histamine type-I receptors (H1-Rs). Its actions
at the α2a-AR have been proposed to play a role in its putative earlier onset of action.
However, it is not known whether mirtazapine is a neutral antagonist or inverse agonist at α2a-
ARs. The current study aimed to determine the mode of α2a-AR antagonism by mirtazapine,
as well as to investigate in vitro the modulatory effects of mirtazapine pre-treatments on β-adrenergic
receptor (β-AR), muscarinic acetylcholine receptor (mAChR) and α2a-AR
functions.
Chinese hamster ovary (CHO-K1) cells expressing the porcine α2a-AR at high numbers (α2a-H),
a constitutively active mutant α2a-AR (α2a--CAM), or mock-transfected control cells (neo)
were radio-labelled with [3H]-adenine and concentration-effect curves of mirtazapine,
yohimbine, mianserin or idazoxan were constructed, measuring [3H]-cAMP accumulation. In
addition human neuroblastoma SH-SY5Y cells and CHO-K1 cells expressing the porcine α2a-
AR at low numbers (am-L) were used to investigate the effect of mirtazapine pre-treatments
on mAChRs and β-ARS or α2a-ARs respectively. After radio-labelling with myo-[2-3H]-inositol
or [2-%]-adenine, radio-label uptake was measured and receptor function was investigated
by constructing concentration-effect curves, measuring [3H]-IPx or [3H]-cAMP accumulation
respectively.
The results from the current study show that mirtazapine binds to the α2a-AR with an affinity
value in the lower micromolar range (K1≈ 0.32 µM; pK1 = 6.50 ± 0.07). Mirtazapine is not a
partial agonist at α2a-ARs as it does not affect [3H]-cAMP accumulation in α2a-H cells.
Preliminary results suggest that mirtazapine displays partial inverse agonism in α2a-CAM
cells, while mianserin displays neutral antagonism. Mirtazapine pre-treatment in SH-SY5Y
cells does not alter muscarinic receptor function (different from fluoxetine and imipramine),
but reduces I-isoproterenol-induced increase in [3H]-cAMP accumulation in SH-SY5Y cells
(typically associated with chronic antidepressant activity). Although inconclusive, the data
also suggests that mirtazapine may reduce α2a-AR function. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/673 |
| Date | January 2004 |
| Creators | Khoza, Kenneth |
| Publisher | North-West University |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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