, Volume 111, Issue 2, pp 169–178 | Cite as

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

  • Clifton W. Callaway
  • Lauren L. Wing
  • David E. Nichols
  • Mark A. Geyer
Original Investigations


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 words

Serotonin Fenfluramine Locomotion Behavior Rats p-Chloroamphetamine 


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  1. Adams LM, Geyer MA (1985) A proposed animal model for hallucinogens based on LSD's effects on patterns of exploration in rats. Behav Neurosci 99:881–900CrossRefPubMedGoogle Scholar
  2. Adell A, Sarna GS, Hutson PH, Curzon G (1989) An in vivo dialysis and behavioural study of the release of 5-HT byp-chloroamphetamine in reserpine-treated rats. Br J Pharmacol 97:206–212PubMedGoogle Scholar
  3. Aulakh CS, Hill JL, Wozniak KM, Murphy DL (1988) Fenfluramine-induced suppression of food intake and locomotor activity is differentially altered by the selective type A monoamine oxidase inhibitor clorgyline. Psychopharmacology 95:313–317CrossRefPubMedGoogle Scholar
  4. Bendotti C, Borsini F, Zanini MG, Samanin R, Garattini S (1980) Effect of fenfluramine and norfenfluramine stereoisomers on stimulant effects ofd-amphetamine and apomorphine in the rat. Pharmacol Res Commun 12:567–574PubMedGoogle Scholar
  5. Bettini E, Ceci A, Spinelli R, Samanin R (1987) Neuroleptic-like effects of thel-isomer of fenfluramine on striatal dopamine release in freely moving rats. Biochem Pharmacol 36:2387–2391CrossRefPubMedGoogle Scholar
  6. Burt DR, Creese I, Snyder SH (1976) Properties of [3H]haloperidol and [3H]dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 12:800–812PubMedGoogle Scholar
  7. Callaway CW, Wing L, Geyer MA (1990) Serotonin release contributes to the stimulant effects of 3,4-methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther 254:456–464PubMedGoogle Scholar
  8. Callaway CW, Johnson MP, Gold LH, Nichols DE, Geyer MA (1991a) Amphetamine derivatives produce locomotor hyperactivity by acting as indirect serotonin agonists. Psychopharmacology 104:293–301PubMedGoogle Scholar
  9. 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
  10. Callaway CW, Rempel N, Peng RL, Geyer MA (1992) Serotonin 5-HT1-like receptors mediate hyperactivity in rats induced by 3,4-methylenedioxymethamphetamine. Neuropsychopharmacology 7:113–127PubMedGoogle Scholar
  11. Dixon WJ (1990) BMDP Biomedical Computer Programs. University of California Press, Los AngelesGoogle Scholar
  12. Fischer JF, Cho AK (1979) Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J Pharmacol Exp Ther 208:203–209PubMedGoogle Scholar
  13. Frey HH, Magnussen MP (1968) Different central mediation of the stimulant effects of amphetamine and itsp-chloro analogue. Biochem Pharmacol 17:1299–1307CrossRefPubMedGoogle Scholar
  14. Fuller RW, Snoddy HD (1980) Effect of serotonin-releasing drugs on serum corticosterone concentration in rats. Neuroendocrinology 31:96–100PubMedGoogle Scholar
  15. Garrattini S, Buczko W, Jori A, Samanin R (1975) The mechanism of action of fenfluramine. Postgrad Med J 51 [Suppl 1]:27–35Google Scholar
  16. Gerson SC, Baldessarini RJ (1980) Motor effects of serotonin in the central nervous system. Life Sci 27:1435–1451CrossRefPubMedGoogle Scholar
  17. Geyer MA, Russo P, Masten V (1986) Multivariate assessment of locomotor behavior: pharmacological and behavioral analyses. Pharmacol Biochem Behav 28:393–399CrossRefGoogle Scholar
  18. Geyer MA, Russo PV, Segal DS, Kuczenski R (1987) Effects of apomorphine and amphetamine on patterns of locomotor and investigatory behavior in rats. Pharmacol Biochem Behav 28:393–399CrossRefPubMedGoogle Scholar
  19. 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
  20. Griffith JD, Nutt JG, Jasinski DR (1975) A comparison of fenfluramine and amphetamine in man. Clin Pharmacol Ther 18:563–570PubMedGoogle Scholar
  21. Hekmatpanah CR, Peroutka SJ (1990) 5-Hydroxytryptamine uptake blockers attenuate the 5-hydroxytryptamine-releasing effects of 3,4-methylenedioxymethamphetamine and related agents. Eur J Pharmacol 177:95–98CrossRefPubMedGoogle Scholar
  22. Hole K, Fuxe K, Jonsson G (1976) Behavioral effects of 5,7-dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways. Brain Res 107:385–399CrossRefPubMedGoogle Scholar
  23. Invernizzi R, Berettera C, Garattini S, Samanin R (1986)d- andl-Isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat. Eur J Pharmacol 120:9–15CrossRefPubMedGoogle Scholar
  24. Jacobs BL, Henriksen SJ, Dement WE (1972) Neurochemical bases of the PGO wave. Brain Res 48:406–411CrossRefPubMedGoogle Scholar
  25. Johnson MP, Conarty PF, Nichols DE (1991) [3H]Monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine andp-chloroamphetamine analogues. Eur J Pharmacol 200:9–16CrossRefPubMedGoogle Scholar
  26. Kannengiesser MH, Hunt PF, Raynaud JP (1976) Comparative action of fenfluramine on the uptake and release of serotonin and dopamine. Eur J Pharmacol 35:35–43CrossRefPubMedGoogle Scholar
  27. Kehne JH, McCloskey TC, Taylor VL, Black CK, Fadayel GM, Schmidt CJ (1992) Effects of the serotonin releasers 3,4-methylenedioxymethamphetamine (MDMA), 4-chloroamphetamine (PCA) and fenfluramine on acoustic and tactile startle reflexes in rats. J Pharmacol Exp Ther 260:78–89PubMedGoogle Scholar
  28. Kleven MS, Schuster CR, Seiden LS (1988) Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine. J Pharmacol Exp Ther 246:822–828PubMedGoogle Scholar
  29. Kostowski W, Gumulka W, Czlonkowski A (1972) Reduced cataleptogenic effects of some neuroleptics in rats with lesioned midbrain raphe and treated withp-chlorophenylalanine. Brain Res 48:443–446CrossRefPubMedGoogle Scholar
  30. Lassen JB (1974) The effect ofp-chloroamphetamine on motility in rats after inhibition of monoamine synthesis, storage, uptake and receptor interaction. Psychopharmacology 34:243–254CrossRefGoogle Scholar
  31. Lichtenberg P, Shapira B, Blacker M, Gropp C, Calev A, Lerer B (1992) Effect of fenlfuramine on mood: a double blind placebo-controlled trial. Biol Psychiatry 31:351–356CrossRefPubMedGoogle Scholar
  32. Lindquist MP, Gotestam KG (1977) Open-field behavior after intravenous amphetamine analogues in rats. Psychopharmacology 55:129–133CrossRefPubMedGoogle Scholar
  33. Lorens SA (1978) Some behavioral effects of serotonin depletion depend on method: a comparison of 5,7-dihydroxytryptamine,p-chlorophenylalanine,p-chloroamphetamine, and electrolytic raphe lesions. Ann NY Acad Sci 305:532–555PubMedGoogle Scholar
  34. Lorens SA, Guldberg HC, Hole K, Kohler C, Srebro B (1976) Activity, avoidance learning, and regional 5-hydroxytryptamine following intra-brain stem 5,7-dihydroxytryptamine and electrolytic midbrain raphe lesons in the rat. Brain Res 108:97–113CrossRefPubMedGoogle Scholar
  35. McGinty DJ, Harper RW (1976) Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res 101:569–575CrossRefPubMedGoogle Scholar
  36. McKenna DJ, Guan XM, Shulgin AT (1991) 3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of3H-dopamine and3H-5-hydroxytryptamine. Pharmacol Biochem Behav 38:505–512CrossRefPubMedGoogle Scholar
  37. 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
  38. Nash JF, Meltzer HY, Gudelsky GA (1988) Elevation of serum prolactin and corticosterone concentrations in the rat after the administration of 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 245:873–879PubMedGoogle Scholar
  39. Neill JC, Cooper SJ (1989) Evidence thatd-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 97:213–218Google Scholar
  40. Nichols DE, Oberlender R (1990) Structure-activity relationships of MDMA and related compounds: a new class of psychoactive drugs? Ann NY Acad Sci 600:613–625PubMedGoogle Scholar
  41. Ogren SO, Johansson C (1985) Separation of the associative and nonassociative effects of brain serotonin released byp-chloroamphetamine: dissociable serotonergic involvement in avoidance learning, pain and motor function. Psychopharmacology 86:12–26CrossRefPubMedGoogle Scholar
  42. Paulus M, Geyer MA (1991) A temporal and spatial scaling hypothesis for the behavioral effects of psychostimulants. Psychopharmacology 104:6–16PubMedGoogle Scholar
  43. Paulus MA, Geyer MA (1992) The effects of MDMA and other methylenedioxy-substituted phenalkylamines on the structure of rat locomotor activity. Neuropsychopharmacology 7:15–31PubMedGoogle Scholar
  44. Raiteri M, Cerrito AM, Cervoni AM, Levi G (1979) Dopamine can be released by two mechanisms differentially affected by the dopamine transport inhibitor nomifensine. J Pharmacol Exp Ther 208:195–202PubMedGoogle Scholar
  45. Samanin R, Ghezzi D, Valzelli L, Garattini S (1972) The effects of selective lesioning of brain serotonin or catecholamine containing neurones on the anorectic activity of fenfluramine and amphetamine. Eur J Pharmacol 19:318–322CrossRefPubMedGoogle Scholar
  46. Sanders-Bush E, Steranka LR (1978) Immediate and long-term effects ofp-chloroamphetamine on brain amines. Ann NY Acad Sci 305:208–221PubMedGoogle Scholar
  47. Schwartz D, Hernandez L, Hoebel BG (1989) Fenfluramine administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as measured by microdialysis. Brain Res 482:261–270CrossRefPubMedGoogle Scholar
  48. Sharp T, Zetterstrom T, Christmanson L, Ungerstedt U (1986)p-Chloroamphetamine releases both serotonin and dopamine into rat brain dialysates in vivo. Neurosci Lett 72:320–324CrossRefPubMedGoogle Scholar
  49. Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364Google Scholar
  50. Steinfels GF, Heym J, Strecker RE, Jacobs BL (1983) Raphe unit activity in freely moving cats is altered by manipulations of central but not peripheral motor systems. Brain Res 279:77–84CrossRefPubMedGoogle Scholar
  51. Trulson ME, Jacobs BL (1976) Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur J Pharmacol 36:149–154CrossRefPubMedGoogle Scholar
  52. Van de Kar LD, Urban JH, Richardson KD, Bethea CL (1985) Pharmacological studies on the serotonergic and nonserotonin-mediated stimulation of prolactin and corticosterone secretion by fenfluramine. Neuroendocrinology 41:283–288PubMedGoogle Scholar
  53. Ward NG, Ang J, Pavinch G (1985) A comparison of the acute effects of dextroamphetamine and fenfluramine in depression. Biol Psychiatry 20:1090–1097CrossRefPubMedGoogle Scholar
  54. Ziance RJ, Sipes IG, Kinnard WJ, Buckley JP (1972) Central nervous system effects of fenfluramine hydrochloride. J Pharmacol Exp Ther 180:110–117PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Clifton W. Callaway
    • 1
  • Lauren L. Wing
    • 2
  • David E. Nichols
    • 3
  • Mark A. Geyer
    • 1
  1. 1.Department of PsychiatryUCSD School of MedicineLa JollaUSA
  2. 2.NIMH Neuroscience CenterSt. Elizabeth's HospitalWashington, DCUSA
  3. 3.Departments of Medicinal Chemistry and Pharmacognosy/Pharmacology and ToxicologySchool of Pharmacy and Pharmacal Sciences, Purdue UniversityLafayetteUSA

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