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In vivo and in vitro interaction of flunarizine with D-fenfluramine serotonergic effects.
Pharmacol Biochem Behav. 1996 Jan; 53(1):155-61.PB

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 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.

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Authors+Show Affiliations

Mennini T
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Gobbi M
No affiliation info available
Crespi D
No affiliation info available
Cinquanta M
No affiliation info available
Frittoli E
No affiliation info available
Giorcelli P
No affiliation info available
Anelli M
No affiliation info available
Caccia S
No affiliation info available

MeSH

AnimalsCalcium-Calmodulin-Dependent Protein Kinase Type 2Calcium-Calmodulin-Dependent Protein KinasesCerebral CortexDopamineDrug InteractionsFenfluramineFlunarizineHydroxyindoleacetic AcidIn Vitro TechniquesMaleRatsRats, Inbred StrainsSerotoninSerotonin Uptake InhibitorsSynaptosomes

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8848445

Citation

Mennini, T, et al. "In Vivo and in Vitro Interaction of Flunarizine With D-fenfluramine Serotonergic Effects." Pharmacology, Biochemistry, and Behavior, vol. 53, no. 1, 1996, pp. 155-61.
Mennini T, Gobbi M, Crespi D, et al. In vivo and in vitro interaction of flunarizine with D-fenfluramine serotonergic effects. Pharmacol Biochem Behav. 1996;53(1):155-61.
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), 155-61.
Mennini T, et al. In Vivo and in Vitro Interaction of Flunarizine With D-fenfluramine Serotonergic Effects. Pharmacol Biochem Behav. 1996;53(1):155-61. PubMed PMID: 8848445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo and in vitro interaction of flunarizine with D-fenfluramine serotonergic effects. AU - Mennini,T, AU - Gobbi,M, AU - Crespi,D, AU - Cinquanta,M, AU - Frittoli,E, AU - Giorcelli,P, AU - Anelli,M, AU - Caccia,S, PY - 1996/1/1/pubmed PY - 2000/3/23/medline PY - 1996/1/1/entrez SP - 155 EP - 61 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol Biochem Behav VL - 53 IS - 1 N2 - 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. SN - 0091-3057 UR - https://www.unboundmedicine.com/medline/citation/8848445/In_vivo_and_in_vitro_interaction_of_flunarizine_with_D_fenfluramine_serotonergic_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0091-3057(95)02010-1 DB - PRIME DP - Unbound Medicine ER -