In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of alpha 2-adrenoceptors on 5-hydroxytryptamine terminals in the rat hippocampus.
The activation of alpha 2-adrenergic heteroreceptors was studied by comparing the effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of CA3 dorsal hippocampus pyramidal neurons prior to, and following, the intravenous administration of noradrenergic agents. Desipramine (2 mg/kg), a selective noradrenaline reuptake blocker, reduced the efficacy of the stimulation; this effect was reversed by the alpha 2-adrenoceptor antagonists yohimbine (0.5 mg/kg) and (-)mianserin (0.5 mg/kg), but not by idazoxan (0.5 mg/kg), an adrenoceptor antagonist with preferential affinity for the imidazoline recognition sites. Low doses of the alpha 2-adrenoceptor agonist clonidine (2 and 10 micrograms/kg) enhanced the efficacy of the stimulation, while high doses (100 and 400 micrograms/kg) reduced it. These incremental and decremental effects of clonidine were reversed by 0.1 and 1 mg/kg of yohimbine, respectively. The enhancing effect of the low dose of clonidine (10 micrograms/kg) was abolished in rats pretreated with the noradrenaline neurotoxin 6-hydroxydopamine. However, the inhibitory effect of a high dose of clonidine (100 micrograms/kg) was unaltered by this pretreatment. These results indicate that low doses of clonidine preferentially activate alpha 2-adrenergic autoreceptors on the noradrenaline neurons resulting in a reduction of the tonic inhibitory effect of endogenous noradrenaline on 5-HT neurotransmission, while higher doses of clonidine would decrease 5-HT neurotransmission through the direct activation of alpha 2-adrenergic heteroreceptors on 5-HT terminals. Furthermore, the selective alpha 2-adrenergic heteroreceptors antagonist (-)mianserin (0.5 mg/kg) increased by itself the efficacy of 5-HT neurotransmission, an effect not observed with yohimbine and idazoxan.(ABSTRACT TRUNCATED AT 250 WORDS)
Mongeau
R
R
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
Blier
P
P
de Montigny
C
C
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D011942:Receptors, Adrenergic, alpha; D012701:Serotonin; D003000:Clonidine; D003891:Desipramine; D009638:Norepinephrine