Role of monoamine oxidase inhibition and monoamine depletion in fenfluramine-induced neurotoxicity and serotonin release

The role of both monoamine synthesis and monoamine oxidase inhibition in me diating the fenfluramine-induced damage to serotonin neurones was examined; as pretreatment agents, both alpha-methyl-para-tyrosine (AMPT) and parachl orophenylalanine (PCPA) were used to deplete dopamine and serotonin, respec tively, while clorgyline and deprenyl were used to inhibit monoamine oxidas e types A and B. While both AMPT and deprenyl did not alter fenfluramine-in duced serotonin or 5-hydroxyindoleacetic acid (5-HIAA) depletion in any are a, PCPA did partially reduce the serotonin depletion in the hippocampus and hypothalamus. Although pretreatment with clorgyline did not significantly alter fenfluramine-induced serotonin depletion, it did produce a 65% mortal ity rate in animals treated with both drugs. Both PCPA and clorgyline signi ficantly increased the depletion of striatal 5-HIAA concentration consequen t to fenfluramine; however, these drugs also produced a long-term depletion of striatal 5-HIAA when administered alone, therefore, the changes seen af ter the coadministration with fenfluramine may be viewed as additive. Final ly, acute PCPA pretreatment attenuated the rapid rise in 3,4-dihydroxypheny lacetic acid (DOPAC) and homovanillic acid (homovanillic acid) induced by f enfluramine, and acute clorgyline reversed the drop in serotonin and rise i n 5-HIAA induced by fenfluramine. These results indicate that the rapid inc rease in dopamine activity induced by fenfluramine is partially dependent o n serotonin concentration and release and that the mechanism of fenfluramin e-induced toxicity is unlike that of the other substituted amphetamines.