Fenfluramine and Brain Serotonin

Clineschmidt, Bradley V.; Zacchei, Anthony G.; Totaro, James A.; Pflueger, A. Barbara; McGuffin, Jodie C.; Wishousky, Theodore I.

doi:10.1111/j.1749-6632.1978.tb31526.x

Cited by 130 publications

(45 citation statements)

References 21 publications

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“…As noted in the Introduction, fluoxetine pretreatment prevents 5-HT depletion associated with highdose FEN administration (Clineschmidt et al 1978;Steranka and Sanders-Bush 1979). This neuroprotective effect involves binding of fluoxetine to SERTs and could occur by at least two mechanisms: 1) blockade of FENinduced 5-HT release; and 2) blockade of FEN accumulation into nerve terminals.…”

Section: Discussionmentioning

confidence: 96%

“…SERTs play a pivotal role in the release process because they serve as 'gateways' for the flow of drug molecules into the cell in exchange for 5-HT molecules that flow out (Levi and Raiteri 1993;Rudnick 1997). Interestingly, 5-HT-selective reuptake inhibitors (SSRIs) such as fluoxetine are known to prevent acute 5-HT release and long-term 5-HT depletion produced by FEN administration (Clineschmidt et al 1978;Steranka and Sanders-Bush 1979;Sabol et al 1992).…”

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confidence: 99%

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1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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“…Because this occurred in animals that showed only intermediate body weight loss (see Results), it is likely that other factors also play a role, for example, a direct effect of the major metabolite of d-fenfluramine, d-norfenfluramine, at postsynaptic 5-HT receptors. Indeed, d-norfenfluramine, not d-fenfluramine, is known to persist relatively long (Clineschmidt et al 1978), and it has affinity for several 5-HT receptors (e.g., Garattini et al 1987). It is conceivable that interactions between body weight loss, 5-HT depletion, and direct effects of d-fenfluramine metabolites underlie the effects of the combination treatment on startle reactivity.…”

mentioning

confidence: 99%

Depletion of 5-HT Disrupts Prepulse Inhibition in Rats Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor

Prinssen

Assié

Koek

et al. 2002

Neuropsychopharmacology

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The 5-HT 1A agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p -chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3 rd PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy- Microdialysis; Serotonin; Prepulse inhibition (PPI) of the startle response refers to the phenomenon that a startle response to a strong stimulus is reduced when this stimulus is preceded by a small prestimulus within a short time period (Graham 1975). The paradigm has gained interest both clinically and preclinically as it was observed that certain patient populations such as schizophrenics, and animals treated with psychotogenics, show attenuated PPI (Swerdlow et al. 1986;Geyer and Braff 1987). Early preclinical pharmacological studies of the mechanisms underlying PPI focused mainly on dopamine, but also on 5-HT, which appears to play an important role. For example, pharmacologically-induced release of 5-HT disrupts PPI in the rat (Padich et al. 1996;Martinez and Geyer 1997). More than one subtype of 5-HT receptor may be involved in these effects as selective stimulation of 5-HT 2A (Sipes and Geyer 1995;Padich et al. 1996), 5-HT 1B Geyer 1994, 1996), and 5-HT 1A receptors (Rigdon and Weatherspoon 1992;Sipes and Geyer 1995) disrupts PPI in the rat. In contrast to the extensive examination of increased function, the effects of de- (Sharp and Hjorth 1990;Blier et al. 1998). The finding that the 5-HT 1A agonist 8-OH-DPAT disrupts PPI after local administration in the raphe nuclei (Sipes and Geyer 1995), the main 5-HT neuron-containing nuclei, suggests that it acts on 5-HT 1A somatodendritic receptors, i.e., via a decrease in 5-HT neurotransmission. Here, we further studied whether decreases in 5-HT levels are indeed able to alter PPI, by examining the effects of chronic, drug-induced, 5-HT depletions. We first examined the effects of repeated administration of the 5-HT synthesis inhibitor p -chlorophenylalanine (PCPA), because this reportedly leads to a large and selective depletion of 5-HT (cf., Koe and Weissman 1966;Sarnek and Baran 1975;Ba...

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“…Since fenfluramine has been shown to exert a selective action on brain 5-hydroxy tryptamine (5-HT, serotonin) concentrations (Opitz 1967;Costa et al, 1971;Duhault and Boulanger, 1977;Clineschmidt et al , 1978), presumably by stimulating the release of 5-HT and blocking its reuptake at the neuronal synapse (Fuxe, 1975), it has been suggested that many of the behavioral changes induced by fenfluramine depend upon alterations in the 5-HT system. For example, it has been shown that 5-hydroxy tryptophan (5-HTP), the precursor of 5-HT, mimics the anorectic (Blundell and Leshem, 1975) and hypothermic (Jespersen and Scheel-Kruger , 1970) effects of fenfluramine.…”

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confidence: 99%

Discriminative stimulus properties of fenfluramine: Evidence for serotonergic involvement

Mcelroy

Feldman

1984

Psychopharmacology

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Fenfluramine and Brain Serotonin

Cited by 130 publications

References 21 publications

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Depletion of 5-HT Disrupts Prepulse Inhibition in Rats Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor

Discriminative stimulus properties of fenfluramine: Evidence for serotonergic involvement

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