Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release
Fenfluramine, a phenalkylamine with serotonin (5-HT) releasing properties, decreases motor activity in rats. The following studies assessed the contribution of 5-HT release to the behavioral effects of fenfluramine and norfenfluramine using a behavioral pattern monitor that simultaneously assesses locomotor and investigatory behavior. First, both fenfluramine and its active metabolited-norfenfluramine dose-dependently reduced locomotor and investigatory activity. The norfenfluramine-induced reduction in activity was not antagonized by pretreatment with the 5-HT uptake inhibitor fluoxetine or the 5-HT synthesis inhibitorp-chlorophenylalanine, drugs that reduce drug-induced 5-HT release. Second, thed- andl-enantiomers of norfenfluramine were nearly equipotent at reducing behavioral activity, althoughd-norfenfluramine is more potent as a 5-HT releasing agent. Third,p-chloroamphetamine, a drug that shares the 5-HT releasing properties of fenfluramine produced locomotor hyperactivity in the same paradigm. Previous studies indicate that other 5-HT releasing phenalkylamines have behavioral effects resembling those ofp-chloroamphetamine rather than those of fenfluramine. Finally, a structurally related drug, 4-methoxy-5-methyl-aminoindan (MMAI), produced dose-dependent reductions in behavioral activity that are similar to the effects of fenfluramine. The behavioral effects of MMAI were not antagonized by fluoxetine or by the 5-HT receptor antagonist methiothepin. These data suggest that the decrease in activity induced by fenfluramine, norfenfluramine and the related drug MMAI is not related to 5-HT release.
Key wordsSerotonin Fenfluramine Locomotion Behavior Rats p-Chloroamphetamine
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- Callaway CW, Nichols DE, Paulus MP, Geyer MA (1991b) Serotonin release is responsible for the locomotor hyperactivity in rats induced by derivatives of amphetamine related to MDMA. In: Fozard JR, Saxena P (eds) Serotonin: molecular biology, receptors and functional effects. Birkhäuser, Basel, pp 491–505Google Scholar
- Dixon WJ (1990) BMDP Biomedical Computer Programs. University of California Press, Los AngelesGoogle Scholar
- Garrattini S, Buczko W, Jori A, Samanin R (1975) The mechanism of action of fenfluramine. Postgrad Med J 51 [Suppl 1]:27–35Google Scholar
- Gotestam KG, Gunne LM (1972) Subjective effects of two anorexigenic drugs fenfluramine and AN448 in amphetamine-dependent subjects. Br J Addict 67:39–44Google Scholar
- Mennini T, Garattini S, Caccia S (1985) Anorectic effect of fenfluramine isomers and metabolites: relationship between brain levels and in vitro potencies on serotonergic mechanisms. Psychopharmacology 85:111–114Google Scholar
- Neill JC, Cooper SJ (1989) Evidence thatd-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 97:213–218Google Scholar
- Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364Google Scholar