In vivo and in vitro interaction of flunarizine with D-fenfluramine serotonergic effects.
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 Ca(2+)-dependent [3H]5-HT release stimulated by 0.5 microM 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 Ca(2+)-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.
Mennini
T
T
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Gobbi
M
M
Crespi
D
D
Cinquanta
M
M
Frittoli
E
E
Giorcelli
P
P
Anelli
M
M
Caccia
S
S
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D005277:Fenfluramine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D005444:Flunarizine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004298:Dopamine; D005277:Fenfluramine; D005444:Flunarizine; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors