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dc.contributor.advisorBrink, C.B.
dc.contributor.advisorHarvey, B.H.
dc.contributor.authorKhoza, Kenneth
dc.date.accessioned2009-02-11T14:27:48Z
dc.date.available2009-02-11T14:27:48Z
dc.date.issued2004
dc.identifier.urihttp://hdl.handle.net/10394/673
dc.descriptionThesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.
dc.description.abstractMirtazapine 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.
dc.publisherNorth-West University
dc.subjectMirtazapineen
dc.subjectAntidepressanten
dc.subjectOnset of actionen
dc.subjectInverse agonismen
dc.subjectNeutral antagonismen
dc.subjectα2A-adrenergic receptorsen
dc.subjectβ-adrenergic receptorsen
dc.subjectMuscarinic acetylcholine receptorsen
dc.titleCharacterisation of the ?2A-adrenoceptor antagonism by mirtazapine and its modifying effects on receptor signallingen
dc.typeThesisen
dc.description.thesistypeMasters


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