Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-
hydroxytryptamine system in the rat brain
N Haddjeri, P Blier and C de Montigny
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Mirtazapine ([(+/-)-MIR], Remeron, ORG 3770) is an alpha-2 adrenoceptor
antagonist endowed with antidepressant activity in humans. The aim of the
present study was to assess the effects of (+/-)-MIR and of its (-
)enantiomer [(-)-MIR] on pre- and postsynaptic alpha-2 adrenoceptors and to
characterize their putative modulation of 5-HT neurotransmission. (+/-)-MIR
(25 micrograms/kg i.v.) enhanced the effectiveness of the electrical
stimulation of the ascending 5-HT pathway by blocking both alpha-2
adrenergic auto- and heteroreceptors. (-)-MIR (10 micrograms/kg i.v.)
enhanced the effectiveness of these stimulations due to a selective action
of (-)-MIR on the alpha-2 heteroreceptors located on 5-HT terminals. Both
(+/-)- and (-)-MIR (500 micrograms/kg i.v.) blocked the suppressant effect
of microiontophoretically applied norepinephrine (NE) on the firing
activity of CA3 dorsal hippocampus pyramidal neurons, indicating their
antagonistic effects on postsynaptic alpha-2 adrenoceptors. (+/-)-MIR (10-
250 micrograms/kg i.v.) enhanced dose-dependently the firing activity of
the 5-HT neurons in naive rats, but not in 6- hydroxydopamine-pretreated
rats. (+/-)-MIR also significantly increased the firing activity of locus
ceruleus NE neurons. In contrast, (-)-MIR (10-250 micrograms/kg i.v.)
failed to change the firing rate of dorsal raphe 5-HT neurons. In
conclusion, these results suggest that both (+/- )-MIR and (-)-MIR are
antagonists at postsynaptic alpha-2 adrenergic receptors, that (+/-)-MIR is
an antagonist of somatodendritic as well as terminal alpha-2 adrenergic
auto- and heteroreceptors, whereas (-)- MIR is a selective antagonist at
alpha-2 adrenergic heteroreceptors. Furthermore, the inhibitory effect of
(-)-MIR on locus ceruleus NE neurons appears to be mediated via 5-HT
neurons because it is abolished by a 5,7-dihydroxytryptamine pretreatment.
Volume 277,
Issue 2,
pp. 861-871,
05/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics
Differences in modulation of noradrenergic and serotonergic transmission by
the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan
TH de Boer, F Nefkens, A van Helvoirt and AM van Delft
Department of Neuropharmacology, N.V. Organon, Oss, The Netherlands.
The effects of three compounds with alpha-2 adrenoceptor antagonistic
properties, mirtazapine (Org 3770; Remeron), mianserin and idazoxan, were
measured on hippocampal noradrenergic and serotonergic transmission in
freely moving rats by using microdialysis. Dihydroxyphenylacetic acid
(DOPAC) was measured as a correlate of noradrenergic presynaptic activity.
Infusing 1 microM tetrodotoxin decreased extracellular serotonin (5-HT) and
DOPAC by 65 and 40%, respectively. 5-Hydroxytryptophan (25 mg/kg s.c.)
increased extracellular 5-HT by 500%, whereas 8-hydroxy-2-(di-n-
propylamino)tetralin hydrobromide (0.5 mg/kg s.c.) decreased 5-HT release
by 60%. Prazosin decreased 5-HT release to 60% of base-line in agreement
with an alpha-1-mediated control of 5-HT transmission, whereas it increased
DOPAC release with 80%. Both mirtazapine (2 and 5 mg/kg s.c.) and idazoxan
(1 mg/kg s.c.) caused a rapid increase in DOPAC by up to 80%. Mianserin
slowly increased DOPAC, reaching a maximal increase of 30 and 60% at 2 and
5 mg/kg s.c., respectively. Only mirtazapine caused a concurrent increase
in 5-HT, reaching up to 80% above base-line within 60 min, whereas
mianserin and idazoxan failed to change 5-HT levels significantly.
Mirtazapine (5 mg/kg s.c.) only slightly affected DOPAC and homovanillic
acid levels in the striatum, hardly affected 5-HT release, but clearly
increased 5- hydroxyindole acetic acid. Thus, the antidepressants
mirtazapine and mianserin markedly differ in their effects on noradrenergic
and serotonergic transmission in vivo as measured with microdialysis in
freely moving rats. These differences are explained by their different
modulatory effects on noradrenergic transmission.
Volume 277,
Issue 2,
pp. 852-860,
05/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics
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