In vivo and in vitro interaction of flunarizine with D-Fenfluramine serotonergic effects

T. Mennini, M. Gobbi, D. Crespi, M. Cinquanta, E. Frittoli, P. Giorcelli, M. Anelli, S. Caccia

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Abstract

Flunarizine (35 mg/kg), but not haloperidol and trifluperazine, counteracted the initial indole depletion induced by D-fenfluramine (dF) in vivo (5 mg/kg), without affecting ex vivo [3H]-serotonin (5-HT) uptake by synaptosomes or changing the brain concentrations of the parent drug and its main active metabolite, D-norfenfluramine (dNF). The long-term indole depletion induced by repeated doses of dF (5 mg/kg, b.i.d. for 4 days) was also reversed by flunarizine pretreatment. Flunarizine, methiothepin, and trifluperazine, but not haloperidol, reduced in vitro the Ca2+-dependent [3H]5-HT release stimulated by 0.5 μM dF and dNF from superfused synaptosomes. At the concentrations used in release experiments the drugs were not active on [3H]5-HT uptake nor on the calcium-calmodulin protein kinase activity, thus excluding an effect on the uptake carrier or on phosphorylation of synaptic proteins involved in exocytosis, respectively. The drugs did not consistently affect [3H]5-HT release induced by depolarization, or dNF-induced [3H]dopamine release in vitro. The fact that flunarizine, as methiothepin and 5-HT uptake inhibitors, counteract dF-induced indole depletion in vivo suggests a relation between the reduction of the Ca2+-dependent release of [3H]5-HT induced by dF in vitro and the protective effect on the short- and long-lasting depletion of indoles induced in vivo by high doses of dF.

Original languageEnglish
Pages (from-to)155-161
Number of pages7
JournalPharmacology, Biochemistry and Behavior
Volume53
Issue number1
DOIs
Publication statusPublished - Jan 1996

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Keywords

  • Calcium-calmodulin protein kinase activity
  • D-Fenfluramine
  • D-Norfenfluramine
  • Dopamine release
  • Flunarizine
  • in ole levels and release
  • Methiothepin
  • Trifluperazine

ASJC Scopus subject areas

  • Biochemistry
  • Behavioral Neuroscience
  • Pharmacology

Cite this

Mennini, T., Gobbi, M., Crespi, D., Cinquanta, M., Frittoli, E., Giorcelli, P., Anelli, M., & Caccia, S. (1996). In vivo and in vitro interaction of flunarizine with D-Fenfluramine serotonergic effects. Pharmacology, Biochemistry and Behavior, 53(1), 155-161. https://doi.org/10.1016/0091-3057(95)02010-1