ACTIVATION OF 5-HT3 RECEPTORS ENHANCES THE ELECTRICALLY-EVOKED RELEASE OF [H-3] NORADRENALINE IN RAT-BRAIN LIMBIC STRUCTURES

The ability of 5-HT receptor agonists to modulate the electrically evoked release of [H-3]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 mu M) concentration-dependently enhanced the electrically evoked release of [H-3]noradrenaline in the hippocampus and the hypothalamus, but only at 100 mu M in the frontal cortex. The enhancing effect of 2-methyl-5-HT was blocked by the 5-HT, 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 [H-3]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 [H-3]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 mu M) to attenuate [H-3]noradrenaline release in the presence of 100 mu M of 2-methyl-5-HT. Moreover, in pseudo-one-pulse experiments 100 mu M Of 2-methyl-5-HT increased [H-3]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 [H-3]noradrenaline. The 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased the release of [H-3]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 [H-3]noradrenaline release, indicating that this effect is not attributable to an action of this 5-HT3 receptor agonist on 5-HT terminals.