Effects of long-term treatment with the alpha 2-adrenoceptor antagonist mirtazapine on 5-HT neurotransmission.
Mirtazapine (ORG 3770, Remeron) is a nonselective alpha 2-adrenoceptor antagonist with antidepressant activity in major depression. The aim of the present study was to assess, using an in vivo electrophysiological paradigm, the effect of long-term treatment with mirtazapine on pre- and postsynaptic alpha 2-adrenoceptors and on 5-HT neurotransmission in male Sprague-Dawley rats. A 21-day treatment with mirtazapine (5 mg/kg/day, s.c., using osmotic minipumps) increased the spontaneous firing activity of locus coeruleus noradrenaline (NA) neurons. Their firing activity was back to normal 48 h after removing the minipump. However, this treatment did not modify the dose-response curve of the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on the firing activity of NA neurons. The spontaneous firing activity of dorsal raphe 5-HT neurons was also markedly increased in mirtazapine-treated rats, and was back to normal 48 h after removing of the minipump. The dose-response curve of the suppressant effect of clonidine on the firing activity of 5-HT neurons was altered in mirtazapine-treated rats. Furthermore, it was further shifted to the left after a 48-h washout. Long-term mirtazapine treatment did not modify the suppressant effects of microiontophoretically-applied NA and 5-HT on the firing activity of CA3 dorsal hippocampus pyramidal neurons. However, this mirtazapine treatment antagonized both the enhancing effect of a low dose (10 micrograms/kg, i.v.) and the reducing effect of a high dose (100 micrograms/kg, i.v.) of the alpha 2-adrenoceptor agonist clonidine on the effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of dorsal hippocampus CA3 pyramidal neurons. After a 48-h washout, only the effect of the high dose of clonidine was attenuated, suggesting a desensitization of the terminal alpha 2-adrenergic heteroreceptor, but not of the terminal alpha 2-adrenergic autoreceptor. The decrease in the effectiveness of the stimulation upon increasing its frequency from 1 to 5 Hz (due to the activation of terminal 5-HT autoreceptors) was unaltered after the long-term mirtazapine treatment. In conclusion, the tonic activation of postsynaptic 5-HT receptor is enhanced by a 21-day treatment with mirtazapine, as a result of a sustained increase in 5-HT neuron firing activity in the presence of decreased function of alpha 2-adrenergic heteroreceptors located on 5-HT terminals in the dorsal hippocampus.
Haddjeri
N
N
Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada.
Blier
P
P
de Montigny
C
C
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078785:Mirtazapine; D009638:Norepinephrine / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008803:Mianserin; D012701:Serotonin; D000078785:Mirtazapine; D009638:Norepinephrine