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Serotonin (5-HT) acts as a neuromodulator and plays a critical role in brain development. Changes in 5-HT signaling during the perinatal period can affect neural development and may result in behavioral changes in adulthood; however, further investigations are necessary including both sexes to study possible differences. Thus, the aim of this study was to investigate the impact of neonatal treatment with fluoxetine on the development of male and female offspring. The animals were divided into four groups according to sex and treatment. The experimental groups received fluoxetine at 10 mg * [kg.sup.-1] (1 [micro]L/g of body weight (bw)) and the animals of control group received saline solution 0.9% (1 [micro]L/g of bw) from postnatal days 1-21. In the neonatal period, reflex ontogeny, somatic development, physical features, and food intake were recorded. In the postnatal period (until day 31) bw and post-weaning food intake were recorded. Chronic administration of fluoxetine in the neonatal period caused a delay in the reflex ontogeny and somatic development, as well as reduction of lactation, post-weaning bw, and post-weaning food intake in rats. No difference was found between the sexes. These changes reaffirm that serotonin plays an important role in regulating the plasticity of the brain during the early development period, but without sex differences. Key words: serotonin, fluoxetine, reflex, growth and development, feeding behavior, sex difference. La serotonine (5-HT) agit comme neuromodulateur et joue un role crucial dans le developpement du cerveau. Des variations dans les voies de signalisation de la 5-HT au cours de la periode perinatale peuvent affecter le developpement neurologique et pourraient entrainer des changements comportementaux a l'age adulte. Cependant, plus de recherches sont necessaires, y compris des etudes portant sur des differences eventuelles entre les sexes. Par consequent, cette etude portait sur l'incidence de l'administration de fluoxetine au cours de la periode neonatale sur le developpement de rejetons males et femelles. Nous avons reparti les animaux dans quatre groupes selon le sexe et le traitement administre. Les groupes experimentaux ont recu de la fluoxetine a 10 mg/kg (1 [micro]l/g de masse corporelle) et les animaux du groupe temoin ont recu une solution saline a 0,9 % (1 [micro]l/g de masse corporelle) de 1 a 21 jours apres la naissance. Au cours de la periode neonatale, nous avons enregistre les parametres suivants: ontogenese des reflexes, developpement somatique, caracteristiques physiques et apport alimentaire. Au cours de la periode postnatale (jusqu'au jour 31) nous avons enregistre la masse corporelle et l'apport alimentaire apres le sevrage. L'administration prolongee de fluoxetine au cours de la periode neonatale a mene a un retard dans l'ontogenie des reflexes et le developpement somatique, une diminution de la masse corporelle avant et apres le sevrage, ainsi que de l'apport alimentaire apres le sevrage. Nous n'avons observe aucune difference entre les sexes. Ces variations reconfirment que la 5-HT joue un role important dans la regulation de la plasticite du cerveau au cours de la periode de developpement precoce, mais sans difference entre les sexes. Mots-cles: serotonine, fluoxetine, reflexe, croissance et developpement, comportements alimentaires, differences entre les sexes., 1. Introduction Serotonin (5-HT) is a widely distributed neuromodulator that plays an important role in regulating brain development (Gaspar et al. 2003). In early developmental periods, it acts as a [...]

Introduction Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive increase in pulmonary arterial pressure with pathologic changes involving vasoconstriction, vascular remodeling, and inflammation, which may lead to [...], Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA-ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA-ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA-ROCK and Akt signalling pathways. Key words: RhoA, Rho kinase, monocrotaline, serotonin transporter, fluoxetine, pulmonary arterial remodeling, Akt. L'activation de la proteine RhoA, une petite GTPase membre de la famille des homologues de Ras, et de ROCK, une kinase associee a ROCK, est importante a la pathogenese de l'hypertension arterielle pulmonaire (HAP). Les inhibiteurs selectifs de recapture de la serotonine peuvent inhiber l'activation de RhoA et ROCK in vitro et ameliorer l'HAP et le remodelage arteriel pulmonaire in vivo. Cependant, on ignore si la voie de signalisation RhoA-ROCK est impliquee dans le traitement de l'HAP in vivo par la fluoxetine. Le but de cette etude etait d'examiner l'implication de la voie de signalisation RhoA-ROCK dans l'effet protecteur exerce par la fluoxetine, un inhibiteur selectif de recapture de la serotonine, sur le remodelage arteriel pulmonaire induit par la monocrotaline (MCT). La MCT a ete donnee a des rats males Wistar afin d' etablir un etat d' HAP. La fluoxetine a ete administree par gavage gastrique une fois par jour pendant 21 jours. Les resultats ont revele que la MCT induisait un remodelage arteriel pulmonaire, accroissait la serotonylation et la translocation membranaire de RhoA dans les poumons et augmentait l' expression du 5-HTT, de RhoA et de ROCK ainsi que la phosphorylation de ERK et Akt dans les arteres pulmonaires et les poumons. La fluoxetine inhibait fortement ces changements induits par la MCT. Ces resultats suggerent que la fluoxetine a inhibe le remodelage arteriel pulmonaire induit par la MCT chez les rats et que ce phenomene impliquait l'inhibition des voies de signalisation RhoA-ROCK et Akt. Mots-cles : RhoA, Rho kinase, monocrotaline, transporteur de serotonine, fluoxetine, remodelage pulmonaire arteriel, Akt. [Traduit par la Redaction]

Objective: To investigate the potential protective effects of amitriptyline and fluoxetine in a catecholamine cell model. Methods: Cultured rat pheochromocytoma (PC12) cells were pretreated with amitriptyline or fluoxetine for 24 [...]

Social isolation (SI) of male mice lasting >4 weeks is associated with aggression toward intruders and a down-regulation of brain allopregnanolone (Allo) content. SI of female mice fails to down-regulate brain Allo content or to induce aggressiveness. Fluoxetine (Prozac in clinical use) is an S- and R-fluoxetine (FLX) mixture, which in mammals is metabolized into S- and R-norfluoxetine (NFLX). The S isomers of FLX and NFLX are more active than their respective R isomers in normalizing brain Allo down-regulation and in reducing the aggressiveness induced by SI. Thus, FLX stereospecifically reduces brain Allo down-regulation and the aggressiveness induced by SI, whereas serotonin (5-HT) uptake inhibition lacks stereospecificity. The doses of S-FLX and S-NFLX that reduce aggressiveness and Allo brain content down-regulation induced by SI are at least one order of magnitude lower than the doses that block 5-HT reuptake. Doses of imipramine that inhibit 5-HT uptake neither reduce aggressiveness nor normalize brain Allo down-regulation. We conclude that Allo brain content normalization is a better candidate than 5-HT reuptake inhibition to explain the reduction of aggressiveness elicited by S-FLX and S-NFLX.

Fluoxetine (Prozac) is the most widely prescribed medication for the treatment of depression. Nevertheless, little is known about the molecular basis of its clinical efficacy, apart from the fact that fluoxetine increases the synaptic availability of serotonin. Here we show that, in vivo, fluoxetine, given either acutely or chronically, regulates the phosphorylation state of dopamine- and cAMPregulated phosphoprotein of [M.sub.r] 32,000 (DARPP-32) at multiple sites in prefrontal cortex, hippocampus, and striatum. Acute administration of fluoxetine increases phosphorylation of DARPP-32 at the protein kinase A site, Thr-34, and at the casein kinase-1 site, Ser-137, and decreases phosphorylation at the cyclin-dependent kinase 5 site, Thr-75. Each of these changes contributes, through distinct signaling pathways, to increased inhibition of protein phosphatase-1, a major serine/threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetinemediated increase in AMPA receptor phosphorylation at Ser-845GluR1 and the beneficial responsiveness to fluoxetine in an animal test of antidepressant efficacy were strongly reduced in DARPP-32 knockout mice, indicating a critical role for this phosphoprotein in the antidepressant actions of fluoxetine. Mice chronically treated with fluoxetine had increased levels of DARPP-32 mRNA and protein and a decreased ability to increase phospho-Ser-137DARPP-32 and phospho-Ser-831-GluR1. These chronic changes may be relevant to the delayed onset of therapeutic efficacy of fluoxetine.

The effects of fluoxetine, phentermine and venlafaxine on pulmonary arterial pressure and electrophysiology were investigated. To this end, the effects of fluoxetine and venlafaxine were compared with those of dexfenfluramine and phentermine on pulmonary arterial pressure and membrane potential. Experimental results showed that fluoxetine, phentermine and venlafaxine have no inhibitory effects on potassium current at the resting membrane potential, suggesting that these agents may present less risk of causing pulmonary hypertension than fenfluramines.

Fluoxetine's effect (30 mg, 60 mg, and placebo) on postcessation weight gain was studied among participants from a randomized, double-blind 10-week smoking cessation trial who met strict criteria for abstinence and drag levels. It was hypothesized that (a) fluoxetine would dose-dependently suppress postcessation weight gain and (b) drug discontinuation would produce dose-dependent weight rebound. During the on-drug phase, placebo participants gained weight linearly (M = 2.61 kg), exceeding both fluoxetine groups (30-mg group M = 1.33 kg, 60-mg group M = 1.25 kg). Weight suppression was initially greater for 60 mg than 30 mg, but both were followed by weight gain. Six months off drag produced greater dose-dependent weight rebound for 60 mg than 30 mg or placebo. Considering both on- and off-drug phases, weight gain for 60 mg of fluoxetine (M = 6.5 kg) was comparable with that for placebo (M = 4.7 kg) but greater than that for 30 mg (M = 3.6 kg). Fluoxetine appears to forestall postcessation weight gain, allowing time for the weight-conscious smoker to focus on quitting smoking rather than on preventing weight gain.

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3[Alpha]-hydroxy-5[Alpha]-pregnane-20-one (3[Alpha]5[Alpha]-ALLO) without altering the brain content of other neurosteroids. ALLO (3[Alpha]5[Alpha] and 3[Alpha]5[Beta] isomers) binds with high affinity to various [Gamma]-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ([approximately]40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.

Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned [5HT.sub.2c] receptors or 5HT receptors encoded by rat cortex mRNA. Responses of [5HT.sub.2C] receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 [[micro]molar] 5HT, the [IC.sub.50] of fluoxetine inhibition was [approximately equal to]20 [[micro]molar]. In accord with the electrophysiological results, fluoxetine inhibited the binding of [3H]5HT to [5HT.sub.2C] receptors expressed in HeLa cells ([K.sub.i] [approximately equal to] 65-97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently ([K.sub.i] [approximately equal to] 56 [[micro]molar]). Our results show that fluoxetine is a competitive and reversible antagonist of [5HT.sub.2C] receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. Similar work may help to design more selective compounds for use in the treatment of brain disorders.

Fluoxetine (Prozac), a widely used antidepressant, is said to exert its medicinal effects almost exclusively by blocking the serotonin uptake systems. The present study shows that both muscle and neuronal nicotinic acetylcholine receptors are blocked, in a noncompetitive and volt-age-dependent way, by fluoxetine, which also increases the rate of desensitization of the nicotinic receptors. Because these receptors are very widely distributed in the both central and peripheral nervous systems, the blocking action of fluoxetine on nicotinic receptors may play an important role in its antidepressant and other therapeutical effects. Our findings will help to understand the mode of action of fluoxetine, and they may also help to develop more specific medicinal drugs.

Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 [micro]mol/kg i.p.) increased the brain content of the neurosteroid 3[Alpha]-hydroxy-5[Alpha]-pregnan-20-one (allopregnanolone, 3[Alpha],5[Alpha]-TH PROG). The increase of brain 3[Alpha],5[Alpha]-TH PROG content elicited by 58 [micro]mol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated ([approximately equal to]3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5[Alpha]-pregnan-3,20-dione (5[Alpha]-dihydroprogesterone, 5[Alpha]-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3[Alpha],5[Alpha]-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3[Alpha],5[Alpha]-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3[Alpha],5[Alpha]-TH PROG brain content. The addition of 10 [[micro]Molar] of 5[Alpha]-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 [[micro]Molar], 15 min) elicited an accumulation of 3[Alpha],5[Alpha]-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3[Alpha],5[Alpha]-TH PROG biosynthesis might be operative in the anxiolytic and antidysphoric actions of this drug.

An analysis of 30 bulimia nervosa outpatients who were administered 60 mg of fluoxetine reveals that bulimic patients with a history of childhood physical abuse score high on the Dissociative Experiences Scale. There is no association between childhood trauma and response to fluoxetine treatment. History of childhood trauma is associated with symptoms such as dissociation and depression, but not with those specific to bulimia nervosa.

Previously researchers have used rat plasma and urine for the detection of drug metabolites. In order to detect the metabolites, high performance liquid chromatography (HPLC) was used. The purpose of [...]