In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of alpha 2-adrenoceptors on 5-hydroxytryptamine terminals in the rat hippocampus

Abstract

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)