Simultaneous Effects of <i>p</i>‐Chloroamphetamine, <i>d</i>‐Fenfluramine, and Reserpine on Free and Stored 5‐Hydroxytryptamine in Brain and Blood

Martín, Francisco Javier Escalada San; Artigas, Francesc

doi:10.1111/j.1471-4159.1992.tb08356.x

Cited by 49 publications

(29 citation statements)

References 38 publications

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“…1). These findings differ from those of Martin and Artigas (1992), who did not observe elevations in plasma 5-HT after administration of (ϩ)-fenfluramine (2.5 mg/kg) to rats. The reason for the discrepancy between our results and those of others is not known but could be related to differences in blood sampling procedures.…”

Section: Discussioncontrasting

confidence: 99%

“…Studies conducted in the 1990s provide little support for this hypothesis. For example, Martin and Artigas (1992) reported that acute administration of (ϩ)-fenfluramine does not increase plasma 5-HT in rats. Moreover, chronic administration of fenfluramine lowers blood 5-HT in humans (see Rothman et al, 2000b and references therein).…”

Section: Discussionmentioning

confidence: 99%

“…Studies conducted in the 1990s indicate that acute administration of (ϩ)-fenfluramine does not increase plasma 5-HT in rats (Martin and Artigas, 1992), and chronic administration of fenfluramine lowers blood 5-HT in humans (see Rothman et al, 2000b and references therein). In the present study, we developed a novel microdialysis method to assess the effects of amphetamine analogs on plasma levels of 5-HT in whole blood samples obtained from conscious catheterized rats.…”

mentioning

confidence: 99%

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

Żółkowska¹,

Rothman²,

Baumann³

2006

J Pharmacol Exp Ther

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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...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Żółkowska¹,

Rothman²,

Baumann³

2006

J Pharmacol Exp Ther

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“…Using microdialysis, it was shown that acute reserpine administration increases the extracellular concentration of 5-HT (Martin and Artigas 1992), which could stimulate 5-HT autoreceptors and decrease 5-HT synthesis through a feedback mechanism (Briley and Moret 1993). This is supported by the findings that acute (Tunnicliff et al 1992) or local (Invernizzi et al 1991) administration of buspirone (a 5-HT1A agonist) reduces 5-HT synthesis.…”

Section: C) 14mentioning

confidence: 89%

The Acute Effects of Reserpine and NSD-1015 on the Brain Serotonin Synthesis Rate Measured by an Autoradiographic Method

Mück‐Šeler

Dikšić

1995

Neuropsychopharmacology

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The rate of serotonin (5-HT) synthesis was measured in the discrete regions of the rat brain utilizing an autoradiographic method and a[ 14 CJ methyl-L-tryptophan as a tracer after an acute treatment with reserpine (10 mg/kg IP) or NSD-1015 (m-hydroxybenzylhydrazine) (100 mg/kg IPIn the 1970s and the 1980s abundant investigations of the central serotoninergic system has led to the conclusion that serotonin (5-HT) plays a role in the regulation 1993 (abstract No. 126.18).

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“…Thirdly, poor metabolisers of fenfluramine derivatives may have a more pronounced exposure to the drug and could be more prone to develop the condition [21]. Lastly, drug-induced alteration of the serotonin pathway might promote the occurrence of PAH [22,23]. By interacting with the serotonin transporter, fenfluramine derivatives release serotonin from platelets and inhibit its reuptake into platelets and pulmonary endothelial cells [22].…”

Section: Discussionmentioning

confidence: 99%

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives

Humbert¹,

Deng²,

Simonneau³

et al. 2002

Eur Respir J

193

115

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This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension.BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations.Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis.In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.

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Simultaneous Effects of p‐Chloroamphetamine, d‐Fenfluramine, and Reserpine on Free and Stored 5‐Hydroxytryptamine in Brain and Blood

Cited by 49 publications

References 38 publications

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

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

The Acute Effects of Reserpine and NSD-1015 on the Brain Serotonin Synthesis Rate Measured by an Autoradiographic Method

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives

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