Org 3770 (mirtazapine, RemeronB) 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 a,-auto-and heteroreceptors controlling noradrenaline and serotonin release. a,-Adrenoceptor antagonism in vivo was confirmed by blockade of clonidine-induced mydriasis and in conditioned taste aversion (CTA) experiments with idazoxan. Blockade of a,-autoreceptors in viva was shown in microdialysis experiments where Org 3770 increased noradrenergic transmission (measured as DOPAC release). Org 3770 has a low affinity for S-HT,, receptors but potently blocks S-HT, and 5-HT3 receptors. Surprisingly, Org 3770 showed 5-HTl,-like effects in CTA and caused lower lip retraction, a 5-HTl, mediated 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 S-HT release. Because Org 3770 blocks 5-HT, and 5-HT3 receptors, only 5-HTl-mediated transmission is enhanced. In conclusion, the noradrenergic activation by a,-autoreceptor-blockade and the consequent indirect enhancement of serotonergic transmission most probably underly the marked therapeutic activity of Org 3770. Blockade of 5-HT2 and 5-HT3 receptors likely prevents side effects associated with non-selective 5-HT activation and may also contribute to the anxiolytic and sleep-improving properties of Org 3770.