Effects of the l isomer of fenfluramine on dopamine mechanisms in rat brain: further studies

Roberto Invernizzi, Rosalia Bertorelli, Silvana Consolo, Silvio Garattini, Rosario Samanin

Research output: Contribution to journalArticlepeer-review

Abstract

Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg.kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5-20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the 1 isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.

Original languageEnglish
Pages (from-to)241-248
Number of pages8
JournalEuropean Journal of Pharmacology
Volume164
Issue number2
DOIs
Publication statusPublished - May 19 1989

Keywords

  • Acetylcholine release in vivo
  • Dopamine metabolism
  • l-Fenfluramine
  • l-Norfenfluramine
  • Nucleus accumbens
  • Striatum

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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