Biochemical investigations into the mode of action of trazodone

Trazodone is an antidepressant drug with well established clinical efficacy in the treatment of depressive disorders, in addition to a marked anxiolytic activity. In contrast to tricyclic, and certain other antidepressant drugs, trazodone has been shown to have no effects on noradrenaline (NA) reuptake mechanisms. Whereas trazodone is a weak inhibitor of the in vitro uptake of [³H]-5-hydroxy-tryptamine (5-HT) into rat occipital cortex synaptosomes, a potent effect shown by this compound is the in vivo occupation of serotonergic [³H]-spiperone binding sites in the mouse frontal cortex; an activity shared by putative 5-HT antagonists and several other antidepressant drugs. The 5-HT antagonist activity of trazodone has been behaviourally verified by the antagonism of the serotonergic head-twitch response elicited by the 5-HT agonist, MK, 212, in mice. Trazodone also interacts with alpha-noradrenergic receptors as assessed by in vitro receptor binding experiments with the radioligands [³H]-WB 4101 and [³H]-dihydroergocryptine (DHE). Ex vivo experiments indicate that, after oral administration to rats, trazodone occupies cortical alpha₂ receptor sites, but with a lower potency than either mianserin or yohimbine. Experiments with superfused rat occipital cortex mini-slices have shown that trazodone can enhance the potassium stimulated and spontaneous efflux of preloaded [³H]-NA. The combination of alpha₂ antagonism and NA releasing properties, in the absence of reuptake inhibition, may be associated with the antidepressant activity of this drug, whereas the potent 5-HT antagonist activity may explain the anxiolytic effects. Finally, trazodone has been found to be devoid of muscarinie receptor affinity as measured by [³H]-quinuclidinyl benzilate (QNB) radioreceptor assays in accord with clinical observation of the absence of anticholinergic side-effects.