Rothman Richard B, Zolkowska Dorota, Baumann Michael H
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland, USA.
Ann N Y Acad Sci. 2008 Oct;1139:268-84. doi: 10.1196/annals.1432.042.
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 For acute treatments, rats received i.v. vehicle or test drug (0.3 and 1.0 mg/kg), and serial blood samples were withdrawn.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 On the last day of infusion, rats received i.v. fenfluramine challenge (1 mg/kg), and serial blood samples were withdrawn.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.
双重多巴胺（DA）/5-羟色胺（5-HT）释放剂是治疗兴奋剂成瘾及其他疾病的有前景的候选药物。然而，某些5-羟色胺转运体（SERT）底物与特发性肺动脉高压（IPAH）和瓣膜性心脏病（VHD）的发生有关。根据“5-HT假说”，SERT底物通过增加血浆5-HT来增加患IPAH和VHD的风险。为了直接验证这一假说，我们测定了急性和慢性使用芬氟拉明及其他SERT配体对雄性大鼠血浆5-HT的影响。对于急性治疗，大鼠静脉注射赋形剂或受试药物（0.3和1.0 mg/kg），并采集系列血样。对于慢性治疗，通过渗透微型泵输注赋形剂或受试药物（3和10 mg/kg/d），持续2周。在输注的最后一天，大鼠静脉注射芬氟拉明激发剂（1 mg/kg），并采集系列血样。使用全血样本的离体微透析法测定血浆5-HT。基线血浆5-HT<1.0 nM。急性注射芬氟拉明或其他SERT底物导致血浆5-HT出现大幅（高达24倍）剂量依赖性升高。3和10 mg/kg/d的慢性芬氟拉明使基线血浆5-HT分别升高1.7倍和3.5倍，而慢性氟西汀则无影响。慢性输注芬氟拉明或氟西汀减弱了急性芬氟拉明升高透析液5-HT的能力，且两种药物均显著降低全血5-HT。急性芬氟拉明使血浆5-HT升高至低于产生不良心血管效应所需的微摩尔水平的浓度。慢性芬氟拉明和氟西汀对血浆5-HT影响极小，这表明与芬氟拉明相关的IPAH风险增加并不取决于血浆5-HT的升高。
