Functional consequences of fenfluramine neurotoxicity.
Male Sprague-Dawley rats were trained to discriminate the anorectic drug d,l-fenfluramine (2.0 mg/kg intraperitoneally administered) from its vehicle using a food-motivated (fixed-ratio 10 schedule) two-lever operant task. Once trained, doses of 0.5, 1.0 and 1.5 mg/kg fenfluramine tested 20 min after IP administration produced dose-responsive discrimination performance. Subsequently, noncontingent twice-a-day administrations of 1 ml/kg saline were made for 4 days and the dose-effect relationship redetermined on the 13th to 15th day after initiation of the chronic saline regimen. Results of these dose-response experiments indicated that there was no significant effect upon fenfluramine discrimination after multiple saline injections or after 10 days without training. Following four days of retraining, 6.25 mg/kg fenfluramine twice-a-day for four days was followed 10 days later by another dose-response determination. This purportedly neurotoxic regimen of fenfluramine significantly increased the rats' ability to discriminate fenfluramine. These results suggest the possibility that chronic release of serotonin or selective damage to serotonin-containing neurons produced by fenfluramine may lead to postsynaptic supersensitivity as manifested by the functionally increased discriminative performance observed.
Schechter
M D
MD
Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown 44272.
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000633:toxicity*; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000523:psychology; D051381:Rats; D011919:Rats, Inbred Strains; D012055:Reinforcement Schedule
D005277:Fenfluramine