AbstractOrg 3770 (mirtazapine, Remeron®) is an antidepressant with an atypical behavioural pharmacology. Org 3770 was found inactive in classical tests used to detect antidepressants, but showed antidepressant‐like effects on REM sleep, in the DRL‐72 (measuring impulse control) and in the (subchronic) bulbectomy model. Org 3770 has no effect on monamine reuptake, but preferentially blocks noradrenergic α2‐auto‐ and heteroreceptors controlling noradrenaline and serotonin release. α2‐Adrenoceptor antagonismin vivowas confirmed by blockade of clonidine‐induced mydriasis and in conditioned taste aversion (CTA) experiments with idazoxan. Blockade of α2‐autoreceptorsin vivowas shown in microdialysis experiments where Org 3770 increased noradrenergic transmission (measured as DOPAC release). Org 3770 has a low affinity for 5‐HT1Areceptors but potently blocks 5‐HT2and 5‐HT3receptors. Surprisingly, Org 3770 showed 5‐HT1A‐like effects in CTA and caused lower lip retraction, a 5‐HT1Amediated effect. Org 3770 increases serotonergic cell‐firing in the dorsal raphe and increased 5‐HT release in the hippocampus as measured by microdialysis. These effects are explained by noradrenergic enhancement of 5‐HT cell firing and blockade of noradrenaline mediated inhibition of hippocampal 5‐HT release. Because Org 3770 blocks 5‐HT2and 5‐HT3receptors, only 5‐HT1‐mediated transmission is enhanced. In conclusion, the noradrenergic activation by α2‐autoreceptor‐blockade and the consequent indirect enhancement of serotonergic transmission most probably underly the marked therapeutic activity of Org 3770. Blockade of 5‐HT2and 5‐HT3receptors likely prevents side effects associated with non‐selective 5‐HT activation and may also contribute to
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