Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs

Mennini, Tiziana; Bizzi, A.; Caccia, Silvio; Codegoni, Anna Maria; Fracasso, Claudia; Frittoli, Emanuela; Guiso, Giovanna; Padura, Ines Martin; Taddei, Carlo; Uslenghi, Angela; Garattini, Silvio

doi:10.1007/bf00169550

Cited by 76 publications

(27 citation statements)

References 33 publications

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“…This explanation is supported by receptor binding experiments. Fenfluramine is metabolized in vivo to norfenfluramine, which has an affinity for 5-HT 2A receptors of 0.3 M (Mennini et al 1991). This concentration is similar to the potency with which both fenfluramine and norfenfluramine produce 5-HT release in in vitro experiments in synaptosomes (Gobbi et al 1998) suggesting that norfenfluramine will occupy a significant fraction of 5-HT 2A receptors at these concentrations.…”

Section: Discussionmentioning

confidence: 66%

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Rice

2001

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 66%

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Rice

2001

Neuropsychopharmacology

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“…The effect of fenfluramine in our study could have been caused by direct binding of this drug to the 5-HT 1A receptor; however, this is not very likely since the affinity of fenfluramine for the 5-HT 1A receptor is very low (mM range) (Mennini et al, 1991). Furthermore, the pharmacological treatments may have affected nonspecific binding.…”

Section: Discussionmentioning

confidence: 67%

Effect of Increased Serotonin Levels on [18F]MPPF Binding in Rat Brain: Fenfluramine vs the Combination of Citalopram and Ketanserin

Haes

Cremers

Bosker

et al. 2005

Neuropsychopharmacol

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[ 18 F]MPPF is a selective serotonin-1A (5-HT 1A ) receptor antagonist and may be used to measure changes in the functional levels of serotonin (5-HT). The technique is based on the assumption that the injected radiolabeled ligand competes for the same receptor as the endogenous transmitter. Results from studies using serotonergic ligands are not always consistent. The aim of the present study was to investigate if [18 F]MPPF binding is decreased after an increase in 5-HT levels.[ 18 F]MPPF binding was assessed in conscious rats using ex vivo autoradiography. We studied the effect of the 5-HT-releasing agent and reuptake inhibitor fenfluramine (10 mg/kg i.p.) and of a combination of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mmol/kg, s.c.) with the 5-HT 2C antagonist ketanserin (100 nmol/kg, s.c). The effect of both treatments on extracellular 5-HT levels was determined using microdialysis. Fenfluramine treatment resulted in a 30-fold increase in extracellular 5-HT levels in the ventral hippocampus and induced a significant reduction of [18 F]MPPF binding in the frontal cortex, hypothalamus, amygdala, and hippocampus. The microdialysis results showed a 10-fold 5-HT increase in the ventral hippocampus after combined administration of ketanserin and citalopram. The combination, however, did not affect [18 F]MPPF binding. Our data show that [18 F]MPPF binding in conscious rats is only reduced after substantial and therefore nonphysiological increases in 5-HT levels. These results may imply that the majority of 5-HT 1A receptors is in the low-affinity state, in vivo.

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“…One alternative interpretation we recognized is that fenfluramine has a direct competitive effect on [ 11 C]AZ10419369 receptor binding. The in the literature reported 5-HT 1A and 5-HT 1B receptor affinity of fenfluramine are, however, in the micro molar range (Mennini et al, 1991). In addition, fenfluramine was reported not to influence the 5-HT 1A receptor binding of the antagonist radioligand […”

Section: Discussionmentioning

confidence: 99%

Confirmation of Fenfluramine Effect on 5-HT_1B Receptor Binding of [¹¹C]AZ10419369 using an Equilibrium Approach

Finnema

Varrone

Hwang

et al. 2011

J Cereb Blood Flow Metab

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Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11 C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11 C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K bol values. The fenfluramine effect on [ 11 C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11 C]AZ10419369 binding potential (BP ND ) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP ND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT 1B receptor radioligand [11 C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11 C]AZ10419369 and PET.

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Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs

Cited by 76 publications

References 33 publications

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Effect of Increased Serotonin Levels on [18F]MPPF Binding in Rat Brain: Fenfluramine vs the Combination of Citalopram and Ketanserin

Confirmation of Fenfluramine Effect on 5-HT_1B Receptor Binding of [¹¹C]AZ10419369 using an Equilibrium Approach

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Comparative studies on the anorectic activity of d-fenfluramine in mice, rats, and guinea pigs

Cited by 76 publications

References 33 publications

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Effect of Increased Serotonin Levels on [18F]MPPF Binding in Rat Brain: Fenfluramine vs the Combination of Citalopram and Ketanserin

Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

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Confirmation of Fenfluramine Effect on 5-HT_1B Receptor Binding of [¹¹C]AZ10419369 using an Equilibrium Approach