In vivo and in vitro interaction of flunarizine with d-fenfluramine serotonergic effects

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 [ 3 H]-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 Ca 2+ -dependent [ 3 H]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 [ 3 H]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 [ 3 H]5-HT release induced by depolarization, or dNF-induced [ 3 H]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 Ca 2+ -dependent release of [ 3 H]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.