Effect of repeated amiflamine administration on serotonergic and noradrenergic neurotransmission: Electrophysiological studies in the rat CNS

Summary Amiflamine is a selective and reversible inhibitor of monoamine oxidase (MAO) type A which exerts a preferential effect on serotonin (5-HT) catabolism. The present studies were undertaken to compare the effects of repeated administration of amiflamine (2 mg/kg, twice daily) on several aspects of the functioning of the 5-HT and norepinephrine (NE) systems in the rat CNS. The activity of MAO-A and B was assessed in forebrain slices and the whole brain contents of the neurotransmitters and their metabolites were determined by HPLC after 2-, 7- and 21-day treatments. MAO-A was inhibited by about 50% 2 h after the last dose and its activity was back to normal in rats sacrificed 12 h after the last dose. The activity of MAO-B was unaffected two or 12 h after the last dose. Whole brain concentration of 5-HT was increased to a greater degree than that of NE following repeated administration of amiflamine. These increases in 5-HT and NE were accompanied by decreased levels of their respective metabolites 5-hydroxy-indoleacetic acid and 3-methoxy-4-hydroxyphenylethyleneglycol. The firing activity of dorsal raphe 5-HT neurons, but not that of NE neurons, was markedl decreased 2–6 h after the last dose of a 2-day treatment. However, 2–6 h after a 21-day treatment, the firing activity of 5-HT neurons was back to normal, whereas that of NE neurons was decreased by 30%. The recovery of firing activity of 5-HT neurons following long-term amiflamine is attributable to a desensitization of the somatic 5-HT autoreceptor as indicated by the decreased responsiveness of 5-HT neurons to intravenous LSD. In contrast, the sensitivity of the somatic NE autoreceptor was not modified, as verified by the unchanged responsiveness of NE neurons to clonidine, an ₂ agonist. The duration of the suppression of firing activity of hippocampus pyramidal neurons produced by the electrical activation of the ascending 5-HT pathway was prolonged in amiflamine-treated rats as compared to controls. This increased synaptic efficacy was attributable to a presynaptic modification since the responsiveness of the same neurons to microiontophoretically-applied 5-HT was not changed. The efficacy of the stimulation of the dorsal NE bundle, as well as that of the microiontophoretic applied of NE, were unchanged in the same rats. Since the efficacy of the stimulation of the 5-HT pathway is increased at the time 5-HT neurons have regained their normal firing rate, it is concluded that 5-HT neurotransmission is enhanced following the long-term treatment with amiflamine.