Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Abstract

Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs (e.g., substituted amphetamines) and prescribed medications (e.g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(Ϯ)-fenfluramine, (Ϯ)-3,4-methylenedioxymethamphetamine, (ϩ)-methamphetamine, (ϩ)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are ϳ0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT.Serotonin (5-hydroxytryptamine, 5-HT) is an endogenous bioactive compound that is widely distributed in neurons, mast cells, enterochromaffin cells, and blood platelets (Cooper et al., 2003;Gershon, 2004). Under normal physiological conditions, plasma 5-HT levels are kept exquisitely low (i.e., Ͻ1 nM) due to transporter-mediated uptake of 5-HT into blood platelets and via metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase (MAO). Included among the many physiological effects of 5-HT are mitogenesis and vasoconstriction. Accordingly, altered regulation of 5-HT levels in blood has been implicated in the pathogenesis of cardiac valvular heart disease (VHD) (Robiolio et al., 1995) and primary pulmonary hypertension (PPH) (MacLean et al., 2000). Many substituted amphetamine analogs (e.g., fenfluramine and aminorex) are substrates for 5-HT transporters (SERTs) and release 5-HT from neurons via reversal of SERT (Rothman et al., 1999). One hypothesis to explain the ability of these agents to increase the risk of developing PPH is that they increase plasma 5-HT by stimulating 5-HT release from platelets (i.e., "the 5-HT hypothesis" of PPH) (MacLean et al., 2000). Others have invoked the same mechanism to explain fenfluramine-induced VHD (Fishman, 1999), although a more likely mechanism in this case involves activation of 5-HT 2B receptors by the N-deethylated metabolite of fenfluramine, norfenfluramine (Rothman et al., 2000...

Role of the Serotonergic System in Reduced Pulmonary Function after Exposure to Methamphetamine

“…The finding that citalopram in vitro was able to partially reverse the effects of MA on MAO-A activity further supports the concept that MA enters epithelial cells via SERT, and this is blocked by the reuptake inhibitor, citalopram. As demonstrated by Zolkowska and colleagues (14), SSRIs may themselves cause transient increases in circulating 5-HT. However, these transient increases resolve within 60 minutes after administration.…”

“…Zolkowska and colleagues (14) reported that intravenous administration of MA in rats resulted in increased plasma 5-HT concentrations. Given 5-HT is an effective bronchoconstrictor and other amphetamine analogs have been shown to inhibit 5-HT metabolism to 5-HIAA (13), we assessed whether 5-HT metabolism was altered in lungs from MA-exposed mice.…”

“…Recently, Zolkowska and colleagues (14) demonstrated that administration of amphetamine analogs, including MA, resulted in significant increases in plasma 5-HT. The elevated 5-HT, as a result of MA administration, was transient, but high enough to potentially stimulate mitogenic responses in pulmonary artery smooth muscle cells (SMCs), suggesting a possible role for the serotonergic system in MA-mediated pulmonary effects.…”

Chronic Fenfluramine Administration Increases Plasma Serotonin (5-Hydroxytryptamine) to Nontoxic Levels

“…Given the uncertainties regarding the validity of the 5-HT hypothesis, we developed a novel microdialysis method to measure plasma levels of 5-HT in whole-blood samples from conscious catheterized rats that involves careful blood handling to minimize the chance of platelet lysis (Zolkowska et al, 2006). Using this method, we reported that baseline dialysate levels of 5-HT in blood are ϳ0.22 nM (or ϳ0.88 nM when corrected for probe recovery), and fenfluramine and other potent SERT substrates evoke transient dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM.…”

Fenfluramine: riddle or Rosetta stone?

“…Plasma 5-HT is increased in rats treated with fenfluramine, or its D-isomer dexfenfluramine [10][11][12]. This may occur because dexfenfluramine blocks uptake of 5-HT by the 5-HTT but if that were the only mechanism of the associated PAH in patients, then the serotonin reuptake inhibitors (SSRIs), such as fluoxetine, which are widely used, would cause PAH.…”