Mennini T, Gobbi M, Crespi D, Cinquanta M, Frittoli E, Giorcelli P, Anelli M, Caccia S
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Pharmacol Biochem Behav. 1996 Jan;53(1):155-61. doi: 10.1016/0091-3057(95)02010-1.
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.
氟桂利嗪（35毫克/千克）可对抗D - 芬氟拉明（dF，体内剂量为5毫克/千克）诱导的初始吲哚耗竭，而氟哌啶醇和三氟拉嗪则无此作用，且不影响离体条件下突触体对[³H] - 血清素（5 - HT）的摄取，也不改变母药及其主要活性代谢物D - 去甲芬氟拉明（dNF）的脑内浓度。重复给予dF（5毫克/千克，每日两次，共4天）诱导的长期吲哚耗竭也可被氟桂利嗪预处理逆转。氟桂利嗪、甲硫哒嗪和三氟拉嗪，而非氟哌啶醇，可在体外降低由0.5微摩尔dF和dNF刺激的、超融合突触体中依赖钙离子的[³H]5 - HT释放。在释放实验所用浓度下，这些药物对[³H]5 - HT摄取以及钙 - 钙调蛋白蛋白激酶活性均无作用，因此分别排除了对摄取载体或对参与胞吐作用的突触蛋白磷酸化的影响。这些药物对去极化诱导的[³H]5 - HT释放或体外dNF诱导的[³H]多巴胺释放并无一致影响。氟桂利嗪与甲硫哒嗪及5 - HT摄取抑制剂一样，可在体内对抗dF诱导的吲哚耗竭，这一事实表明，体外dF诱导的依赖钙离子的[³H]5 - HT释放减少与高剂量dF在体内诱导的吲哚短期和长期耗竭的保护作用之间存在关联。
