Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Claassen, V.; Davies, Julia; Hertting, G.; Placheta, P

doi:10.1111/j.1476-5381.1977.tb07528.x

Cited by 173 publications

(57 citation statements)

References 18 publications

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“…And 5-HT neurotransmission in brain slices prepared from the rat hypothalamus shows time-dependent difference between the dark phase and the light phase (Blier et al, 1989). Furthermore, it is thought that the reuptake of 5-HT from the synapse cleft is inhibited almost completely by injection with 30 mg/kg fluvoxamine at any time (Claassen et al, 1977). Nevertheless, extracellular 5-HT levels could be further increased by the injection of fluvoxamine at 9:00 PM than at 9:00 AM.…”

Section: Figmentioning

confidence: 87%

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

Ushijima

Sakaguchi

Sato

et al. 2005

J Pharmacol Exp Ther

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The influence of dosing time on the anti-immobility effect of antidepressants and mechanisms underlying this phenomenon were investigated in mice. In the forced swimming test (FST), the immobility time of mice treated with amitriptyline (15 mg/kg) and fluvoxamine (30 mg/kg) showed a significant 24-h rhythm. The anti-immobility effect of fluvoxamine in FST was potent at the early part of the dark phase without increasing locomotor activity. Concerning pharmacokinetics, although K e of fluvoxamine was approximately 1.3-fold higher in mice injected with fluvoxamine at 9:00 PM than at 9:00 AM, no dosing time dependence was demonstrated for either plasma or brain fluvoxamine concentration at 0.5 h after the drug injection. On the other hand, serotonin transporter (SERT) mRNA expression and 5-hydroxytryptamine (5-HT) uptake activity in the mouse midbrain showed significant time-dependent changes with higher levels during the dark phase and lower levels during the light phase. These results suggest that the reuptake of 5-HT might be more increased during the dark phase. Since the reuptake of 5-HT is inhibited almost completely by injection with 30 mg/kg fluvoxamine at any time, the extracellular 5-HT level may be more increased by the injection of fluvoxamine at the early part of the dark phase. The present results suggest that the antiimmobility effect of fluvoxamine in FST increases depending on dosing time. Furthermore, the time-dependent change of SERT mRNA expression and uptake activity in the midbrain is suggested to be the mechanism underlying the 24-h rhythm of anti-immobility effect of fluvoxamine.

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Section: Figmentioning

confidence: 87%

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

Ushijima

Sakaguchi

Sato

et al. 2005

J Pharmacol Exp Ther

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“…Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and harvested for membrane preparation by homogenization in buffer (ice-cold 50 mM Tris, pH 7.4, with 1ϫ Complete protease inhibitor cocktail; Roche Molecular Systems, Inc., Alameda, CA). The structures of all ligands used in this study have been published previously (Claassen et al, 1977;Wong et al, 1993;Partilla et al, 2000;White et al, 2005;Ravna et al, 2006b) and are presented in Fig. 1.…”

Section: Methodsmentioning

confidence: 99%

Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Martin

Henningsen²,

Suen³

et al. 2008

J Pharmacol Exp Ther

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Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [ 3 H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal ⅐ mol Ϫ1 ), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (⌬H O ) and entropy (ϪT⌬S O )contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% ⌬G O ) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.Inhibitors of the serotonin transporter (SERT) have long been in clinical use for treatment of depression and anxiety, predating even the molecular identification of the target (Blakely et al., 1991). As such, SERT is the target of a large number of clinically proven drugs from diverse chemotypes (Fig. 1) that act by blocking transit of 5-hydroytryptamine (serotonin) (5-HT) through the transporter. Many reports describe the equilibrium binding properties of members of this class of drugs with SERT as well as potency for inhibition of 5-HT reuptake (Blakely et al., 1994;Tatsumi et al., 1997;Nemeroff and Owens, 2003;Rothman and Baumann, 2003). Although the three-dimensional structure of SERT has not yet been elucidated, crystal structures have been determined for other members of the 12 transmembrane domain major facilitator superfamily. Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al., 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al., 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors wer...

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“…Preliminary studies (A.M. Johnson, personal communication) indicate that paroxetine can, as other 5-HT uptake inhibitors (Fuller et al, 1974;Claassen et al, 1977;Ross et al, 1981), decrease 5-HT turnover in rat brain. However, it is not known whether it is capable of enhancing 5-HT synthesis by increasing tryptophan availability to the brain secondarily to inhibition of activity of the major tryptophan-degrading enzyme, liver tryptophan pyrrolase (tryptophan 2,3-dioxygenase, EC 1.13.11.11), as can 20 other antidepressants of different chemical structures and pharmacological classes (Badawy & Evans, 1981;1982;Badawy, 1986).…”

Section: Introductionmentioning

confidence: 99%

Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat

Badawy

Morgan

1991

British J Pharmacology

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1 The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat. 2 Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg-dose. 3 Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine. 4 Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase-inhibitory mechanism. Cerebral 5-hydroxytryptamine (5-HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg -. With larger doses, decreased 5-HT turnover, probably as a result of 5-HT uptake inhibition, was the more dominant feature. 5 Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non-esterified fatty acids or glucose. 6 It is concluded that, in addition to inhibiting brain 5-HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5-HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.

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Fluvoxamine, a Specific 5‐hydroxytryptamine Uptake Inhibitor

Cited by 173 publications

References 18 publications

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice

Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat

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