Fenfluramine-induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS.
Previous studies have implicated a role for nitric oxide (NO) and peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity. The present study was undertaken to investigate whether NO is involved in serotonergic neurotoxicity caused by fenfluramine. In the first experiment, the effect of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 25 mg/kg x 4) on fenfluramine (25 mg/kg x 4)-induced serotonergic neurotoxicity in Swiss Webster mice was investigated. In the second experiment, the effect of fenfluramine (25 mg/kg x 4) on nNOS (-/-) and wild-type (WT) mice was investigated. Fenfluramine induced hypothermia in all three mouse strains, and 7-NI had no thermoregulatory effect. Selective depletion of 5-HT and 5-HT transporter binding sites in the striatum, frontal cortex and hippocampus in all three mouse strains was observed, with no evidence of dopaminergic neurotoxicity. In the first experiment, 7-NI did not attenuate serotonergic neurotoxicity in Swiss Webster mice. In the second experiment, nNOS(-/-) and WT mice were equally sensitive to serotonergic neurotoxicity. These findings suggest that NO and peroxynitrite do not mediate fenfluramine-induced serotonergic neurotoxicity, and that NO is a selective mediator of amphetamines-induced dopaminergic neurotoxicity.
Itzhak
Yossef
Y
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, Florida, USA. yitzhak@med.miami.edu
Ali
Syed F
SF
Anderson
Karen L
KL
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000032:analysis; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005277:Fenfluramine / Q000633:toxicity*; D005625:Frontal Lobe / Q000737:chemistry / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D012701:Serotonin / Q000032:analysis; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*
D015415:Biomarkers; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005277:Fenfluramine; D007191:Indazoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C496321:Nos1 protein, mouse; C080122:7-nitroindazole