title: Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine.
abstract: Fenfluramine is an anorectic agent in clinical use that is believed to act by enhancing 5-hydroxytryptamine (5-HT) neurotransmission. Tolerance to the anorectic properties of fenfluramine develops rapidly and long-lasting depletions of brain 5-HT have been reported to occur after repeated administration. It is possible that tolerance to fenfluramine may be related to the 5-HT depletions. Rats (n = 96), previously allowed to drink sweetened condensed milk during daily 15-min sessions, were treated with fenfluramine (6.25 mg/kg/12 hr x 4 days) or saline. Two or 8 weeks later rats were administered fenfluramine acutely (0, 1.25, 6.25 or 12.5 mg/kg; n = 6/group), tested for milk intake and sacrificed 2 hr later. Brains were removed and regions assayed for dopamine, 5-HT and metabolites. Acute administration of fenfluramine produced a dose-dependent decrease in milk intake and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in cortex, hypothalamus and hippocampus. Tolerance to the effects of acute fenfluramine on milk intake was observed in rats at 2 weeks (ED50 = 3.24 vs. 6.37 mg/kg; saline vs. fenfluramine pretreatment, respectively) and, to a lesser extent, at 8 weeks (ED50 = 2.99 vs. 4.04 mg/kg; saline vs. fenfluramine pretreatment) after the 4-day regimen of fenfluramine. Levels of 5-HT and 5-HIAA in somatosensory cortex, hypothalamus, striatum and hippocampus were depleted significantly 2 weeks after the last daily fenfluramine injection. The acute 5-HT depleting effect of fenfluramine was markedly attenuated in these regions 2 weeks after the 4-day regimen of fenfluramine.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois.
authors: M S
authors: MS
authors: Kleven
authors: C R
authors: CR
authors: Schuster
authors: L S
authors: LS
authors: Seiden
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008892:Milk; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
chemical_list: D001067:Appetite Depressants; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine