Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine.
The optical isomers of fenfluramine and norfenfluramine were administered to rats to examine their relative potency for destruction of serotonin neurons. Rats were sacrificed one week following a single 10 mg/kg SC injection of one of the four compounds and monoamine and metabolite levels in the frontal cortex and hippocampus brain regions were examined by HPLC-EC techniques. In addition, [3H]-paroxetine binding to homogenates of these brain regions was determined. With the exception of hippocampal 5-HT levels following d-fenfluramine treatment, there was a decrease in all the serotonergic markers assayed, following treatment with the d-enantiomers of fenfluramine and norfenfluramine. No decrease in any serotonergic marker was seen at this dose following treatment with the l-enantiomers of fenfluramine or norfenfluramine. Also, none of the drug treatments resulted in a significant decrease in catecholamines or their metabolites. With all the serotonergic markers examined, d-norfenfluramine was found to cause a significantly greater decrease than d-fenfluramine. The significance of these results is discussed in terms of the hypothesis that the long-term serotonergic deficits observed with d-fenfluramine may result from its metabolite, d-norfenfluramine.
Johnson
M P
MP
Department of Pharmacology, Purdue University, West Lafayette, IN 47907.
Nichols
D E
DE
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000633:toxicity*; D005625:Frontal Lobe / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009642:Norfenfluramine / Q000633:toxicity*; D017374:Paroxetine; D010880:Piperidines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism
D015306:Biogenic Monoamines; D010880:Piperidines; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin; D017374:Paroxetine