Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine

Johnson, Michael P.; Nichols, David E.

doi:10.1016/0091-3057(90)90133-3

Cited by 47 publications

(8 citation statements)

References 28 publications

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“…In these experiments, we compared the effects of d -fenfluramine, mCPP and TFMPP, but also included the metabolite d -norfenfluramine, since this metabolite has been implicated in the 5-HT depletion produced by d -fenfluramine observed in vivo (Caccia et al , 1993; Johnson and Nichols, 1990). Consistent with our previous findings (Rothman et al , 2001), d -fenfluramine and d -norfenfluramine evoked the release of preloaded [ 3 H]5-HT from synaptosomes.…”

Section: Resultsmentioning

confidence: 99%

“…As a means to compare the molecular mechanism of action for d -fenfluramine and phenylpiperazines, we examined the ability of the drugs to evoke release of preloaded [ 3 H]5-HT and [ 3 H]dopamine in rat brain synaptosomes. In these experiments, we also included the N -deethylated metabolite of d -fenfluramine, d -norfenfluramine, because this compound has been implicated in the 5-HT deficits produced by d -fenfluramine administration in rats (Caccia et al , 1993; Johnson and Nichols, 1990). Our release experiments clearly demonstrate that d -fenfluramine, d -norfenfluramine, mCPP and TFMPP are fully efficacious in their ability to release [ 3 H]5-HT (Fig.3a-d), with minimal effects on release of [ 3 H]dopamine.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Baumann

Bulling²,

Benaderet

et al. 2013

Neuropsychopharmacol

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Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Baumann

Bulling²,

Benaderet

et al. 2013

Neuropsychopharmacol

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“…The isomer dl-fenfluramine, which acts on the dopaminergic and serotonergic systems, appears to result in more side effects than d-fenfluramine, which has only a serotonergic action (10,11). Thus, d-fenfluramine appears to be more efficient in its anorectic action and less harmful than the other forms of the drug (10,12).…”

Section: Introductionmentioning

confidence: 91%

Chronic fenfluramine treatment of rats with different ages: Effects on brain oxidative stress-related parameters

D’Almeida

Camarini

Azzalis

et al. 1996

J. Biochem. Toxicol.

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“…Studies with high doses of FEN and its major metabolite, norfenfluramine (norFEN), in animals including nonhuman primates, have shown neurotoxic effects. The FEN-and norFEN-induced neurotoxic effects included long-lasting decreases of tryptophan hydroxylase activity, contents of indoles and 5-HT transporters, and destruction of 5-HT neuron terminals (Caccia et al, 1993;Clineschmidt et al, 1978;Clausing et al, 1998;Colado et al, 1997;De Souza et al, 1991;Gobbi et al, 1996;Harvey et al, 1997;Johnson and Nichols, 1990;Kleven and Seiden, 1989;McCann et al, 1995McCann et al, , 1997Mennini et al, 1996;Rowland and Carlton, 1986;Sabol et al, 1992;Stewart et al, 1997;Yeh, 1997a;Zaczek et al, 1990). Like other amphetamines [(3,, and methamphetamine (MA)], FEN also induced hyperthermia at ambient temperature (23°C) in rabbits (Quock and Weick, 1979), and in rodents above 26°C (Clausing et al, 1998;Malberg and Seiden, 1997;Preston et al, 1990;Stewart et al, 1997).…”

Section: Introductionmentioning

confidence: 94%

Effects of antihistamines on fenfluramine-induced depletion of indoles in the brain of rats

Yeh¹

1999

Synapse

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Various effects of chlorpheniramine (CPA), diphenhydramine (DIPH), tripelennamine (TRIP), and pyrilamine (PYRI) on fenfluramine (FEN)-induced depletion of serotonin in the brain of rats were observed to be dependent on body temperature. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, and striatum of rats treated with FEN (10 mg/kg, once or twice daily x 4 days) decreased to approximately 30% (P < 0.01) that of controls with no significant changes after CPA, DIPH, TRIP, and PYRI. Treatment with FEN plus CPA (5, 10, 20 mg/kg) and FEN plus DIPH (20 mg/kg), but not FEN plus TRIP (20 mg/kg) and FEN plus PYRI (20 mg/kg), increased brain serotonin levels 2- to 3-fold more than those treated with FEN plus saline. Treatment with FEN plus CPA and FEN plus DIPH, but not FEN plus TRIP and FEN plus PYRI, decreased rectal temperature with no significant change after FEN. The antihistamines alone decreased temperature at a 1-hour period and enhanced FEN-induced reduction in body weight. Possible mechanisms of the different effects of antihistamines on FEN-induced depletion of serotonin are discussed.

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Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine

Cited by 47 publications

References 28 publications

Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Chronic fenfluramine treatment of rats with different ages: Effects on brain oxidative stress-related parameters

Effects of antihistamines on fenfluramine-induced depletion of indoles in the brain of rats

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