title: Activation of 5-HT3 receptors enhances the electrically evoked release of [3H]noradrenaline in rat brain limbic structures.
abstract: The ability of 5-HT receptor agonists to modulate the electrically evoked release of [3H]noradrenaline was tested on preloaded slices of the rat brain. The 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) (10-100 microM) concentration-dependently enhanced the electrically evoked release of [3H]noradrenaline in the hippocampus and the hypothalamus, but only at 100 microM in the frontal cortex. The enhancing effect of 2-methyl-5-HT was blocked by the 5-HT3 receptor antagonist ondansetron. Elevated levels of endogenous 5-HT, achieved through selective reuptake blockade with paroxetine, as well as the addition of exogenous 5-HT in the medium, also enhanced [3H]noradrenaline release. Furthermore, this effect of paroxetine was blocked by nanomolar concentrations of the 5-HT3 receptor antagonists ondansetron, tropisetron and (S)-zacopride. Only high concentrations of the 5-HT3 receptor agonist m-chlorophenylbiguanide increased [3H]noradrenaline release from hippocampal slices, and this effect was not blocked by ondansetron nor by (S)-zacopride. The possibility that the enhancing effect of 2-methyl-5-HT could have been due to the antagonism of alpha 2-autoreceptors of noradrenergic terminals was ruled out by the unaltered effectiveness of the alpha 2-adrenoceptor agonist UK-14,304 (1 microM) to attenuate [3H]noradrenaline release in the presence of 100 microM of 2-methyl-5-HT. Moreover, in pseudo-one-pulse experiments 100 microM of 2-methyl-5-HT increased [3H]noradrenaline release in the absence of autoinhibition through alpha 2-adrenergic autoreceptors. The 5-HT1A and 5-HT1B receptor agonists 8-hydroxy-2(di-n-propyl-amino)tetralin and CP-93,129, respectively, as well as the 5-HT1 receptor agonist 5-carboxyamidotryptamine, were devoid of effect on the release of [3H]noradrenaline. The 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased the release of [3H]noradrenaline, but this effect was not blocked with the 5-HT3 receptor antagonist ondansetron. Lesioning 5-HT fibers with the neurotoxin 5,7-dihydroxytryptamine did not alter the action of 2-methyl-5-HT on [3H]noradrenaline release, indicating that this effect is not attributable to an action of this 5-HT3 receptor agonist on 5-HT terminals.
authors.affiliation: Department of Psychiatry, McGill University, Montréal, Québec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Mongeau
authors.forename: C
authors.initials: C
authors.lastname: De Montigny
authors.forename: P
authors.initials: P
authors.lastname: Blier
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D005071:Evoked Potentials; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D017294:Ondansetron; C045918:2-methyl-5-HT; D009638:Norepinephrine