Serotonin (5-HT) Transporter Ligands Affect Plasma 5-HT in Rats Implications for Medication Development
Serotonin (5-HT) Transporter Ligands Affect Plasma 5-HT in Rats Implications for Medication Development
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DOI：
10.1196/annals.1432.042
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发表时间：
2008-01-01
期刊：
影响因子：
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通讯作者：
Baumann, Michael H.
中科院分区：
文献类型：
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作者：
Rothman, Richard B.;Zolkowska, Dorota;Baumann, Michael H.
多巴胺（DA）/5-羟色胺（5-HT）双重释放剂是治疗兴奋剂成瘾和其他疾病的有希望的候选药物。然而，某些5-HT转运蛋白（SERT）底物与特发性肺动脉高压（IPAH）和瓣膜性心脏病（VHD）的发生相关。根据“5-HT假说”，SERT底物通过增加血浆5-HT来增加IPAH和VHD发展的风险。为了直接测试这一假说，我们确定了急性和慢性芬氟拉明和其他SERT配体对雄性大鼠血浆5-HT的影响。对于急性给药，大鼠静脉注射溶媒或试验药物（0.3和1.0 mg/kg），并采集系列血样。对于长期治疗，通过渗透微型泵（3和10 mg/kg/d）输注溶剂或试验药物2周。在输注的最后一天，大鼠接受静脉芬氟拉明攻击（1 mg/kg），并抽取系列血样。使用离体微透析法测定全血样品中的血浆5-HT。基线血浆5-HT < 1.0 nM。急性注射芬氟拉明或其他SERT底物引起血浆5-HT的大（高达24倍）剂量依赖性增加。慢性芬氟拉明3和10 mg/kg/d使基线血浆5-HT增加1.7和3.5倍，而慢性氟西汀无影响。长期输注芬氟拉明或氟西汀降低了急性芬氟拉明升高透析液5-HT的能力，两种药物均显著降低了全血5-HT。急性芬氟拉明使血浆5-HT浓度升高至低于产生不良心血管效应所需的微摩尔水平。慢性芬氟拉明和氟西汀对血浆5-HT的影响很小，这表明芬氟拉明相关的IPAH风险增加并不依赖于血浆5-HT的升高。
Dual dopamine (DA)/serotonin (5-HT)-releasing agents are promising candidate medications for stimulant addiction and other disorders. However, certain 5-HT transporter (SERT) substrates are associated with development of idiopathic pulmonary arterial hypertension (IPAH) and valvular heart disease (VHD). According to the "5-HT hypothesis," SERT substrates increase the risk for developing IPAH and VHD by increasing plasma 5-HT To test this hypothesis directly, we determined the effects of acute and chronic fenfluramine, and other SERT ligands, on plasma 5-HT in male rats. For acute treatments, rats received i.v. vehicle or test drug (0.3 and 1.0 mg/kg), and serial blood samples were withdrawn. For chronic treatments, vehicle or test drug was infused via osmotic minipump (3 and 10 mg/kg/d) for 2 weeks. On the last day of infusion, rats received i.v. fenfluramine challenge (1 mg/kg), and serial blood samples were withdrawn. Plasma 5-HT was measured using ex vivo microdialysis in whole-blood samples. Baseline plasma 5-HT was < 1.0 nM. Acute injection of fenfluramine or other SERT substrates caused large (up to 24-fold) dose-dependent increases in plasma 5-HT Chronic fenfluramine at 3 and 10 mg/kg/d produced 1.7- and 3.5-fold increases in baseline plasma 5-HT, while chronic fluoxetine had no effect. Chronic infusions of fenfluramine or fluoxetine diminished the ability of acute fenfluramine to elevate dialysate 5-HT, and both drugs markedly reduced whole-blood 5-HT Acute fenfluramine increases plasma 5-HT to concentrations that are below the micromolar levels necessary to produce adverse cardiovascular effects. Chronic fenfluramine and fluoxetine have minimal effects on plasma 5-HT, suggesting that the increased risk for IPAH associated with fenfluramine does not depend upon elevations in plasma 5-HT.