Effect of the reversible monoamine oxidase-A inhibitor befloxatone on the rat 5-hydroxytryptamine neurotransmission

The aim of the present study was to assess, using in vivo electrophysiological paradigms, the effect of sustained administration of the selective and reversible monoamine oxidase-A inhibitor beflotaxone on serotonin (5-hydroxytryptamine, 5-HT) neurotransmission. In male Sprague-Dawley rats with the osmotic minipumps in place, a treatment with befloxatone (0.75 mg/kg per day, s.c.) for 2 days decreased the spontaneous firing activity of dorsal raphe 5-HT neurons. The combination of befloxatone and the 5-HT1A/1B receptor antagonist (-)-pindolol (15 mg/kg per day, s.c.) for 2 days slightly increased the firing activity of 5-HT neurons, whereas a treatment with (-)-pindolol alone for 2 days did not modify this parameter. The suppressant effects on the firing activity of 5-HT neurons of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD), injected intravenously, and of both 5-HT and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), applied by microiontophoresis, were attenuated in rats treated with befloxatone for 2 days, suggesting an early desensitization of the somatodendritic 5-HT1A receptors. The firing activity of 5-HT neurons was back to normal after a treatment for 21 days with befloxatone but the suppressant effects of LSD, 5-HT or 8-OH-DPAT was the same as in controls. In contrast, the suppressant effect of the alpha(2)-adrenoceptor agonist clonidine on the firing activity of 5-HT neurons was significantly attenuated after the treatment with befloxatone for 21 days. At the postsynaptic level, the administration of the selective 5-HT1A receptor antagonist (N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride (WAY 100635, 100 mu g/kg, i.v.) did not modify the firing activity of quisqualate-activated dorsal hippocampus CA(3) pyramidal neurons in control rats. In contrast, in rats treated with befloxatone in combination with (-)-pindolol for 2 days as well as with befloxatone alone for 21 days, WAY 100635 significantly increased the firing of CA(3) pyramidal neurons. In conclusion, these data suggest that when the firing activity of 5-HT neurons is normal in the presence of befloxatone, either after a two-day treatment together with (-)-pindolol or alone for 21 days, the tonic activation of postsynaptic 5-HT1A receptors is enhanced. (C) 1998 Elsevier Science B.V.