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Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release

Abstract

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.

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Correspondence to Mark A. Geyer.

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Callaway, C.W., Wing, L.L., Nichols, D.E. et al. Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release. Psychopharmacology 111, 169–178 (1993). https://doi.org/10.1007/BF02245519

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Key words

  • Serotonin
  • Fenfluramine
  • Locomotion
  • Behavior
  • Rats
  • p-Chloroamphetamine