Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

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 For acute treatments, rats received i.v. vehicle or test drug (0.3 and 1.0 mg/kg), and serial blood samples were withdrawn.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 On the last day of infusion, rats received i.v. fenfluramine challenge (1 mg/kg), and serial blood samples were withdrawn.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.