Premium
The α 2 ‐selective adrenoceptor antagonist org 3770 (mirtazapine, Remeron®) enhances noradrenergic and serotonergic transmission
Author(s) -
De Boer Th.,
Ruigt G. S. F.,
Berendsen H. H. G.
Publication year - 1995
Publication title -
human psychopharmacology: clinical and experimental
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.461
H-Index - 78
eISSN - 1099-1077
pISSN - 0885-6222
DOI - 10.1002/hup.470100805
Subject(s) - serotonergic , idazoxan , microdialysis , dorsal raphe nucleus , autoreceptor , chemistry , serotonin , agonist , pharmacology , neuroscience , medicine , endocrinology , receptor , antagonist , psychology , biology , prazosin , central nervous system , biochemistry
Org 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 α 2 ‐auto‐ and heteroreceptors controlling noradrenaline and serotonin release. α 2 ‐Adrenoceptor antagonism in vivo was confirmed by blockade of clonidine‐induced mydriasis and in conditioned taste aversion (CTA) experiments with idazoxan. Blockade of α 2 ‐autoreceptors in vivo was shown in microdialysis experiments where Org 3770 increased noradrenergic transmission (measured as DOPAC release). Org 3770 has a low affinity for 5‐HT 1A receptors but potently blocks 5‐HT 2 and 5‐HT 3 receptors. Surprisingly, Org 3770 showed 5‐HT 1A ‐like effects in CTA and caused lower lip retraction, a 5‐HT 1A 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 5‐HT release. Because Org 3770 blocks 5‐HT 2 and 5‐HT 3 receptors, only 5‐HT 1 ‐mediated transmission is enhanced. In conclusion, the noradrenergic activation by α 2 ‐autoreceptor‐blockade and the consequent indirect enhancement of serotonergic transmission most probably underly the marked therapeutic activity of Org 3770. Blockade of 5‐HT 2 and 5‐HT 3 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.