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Single pump column switching technique employing a flow gradient and wavelength programmed fluorescence for simultaneous monitoring of serotonin, fluoxetine and norfluoxetine in rat brain microdialysate.

Ramaiya A, March C, Karnes HT.

Department of Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0533, USA.

A single pump column switching technique with multidimensional chromatography, flow gradient and wavelength programmed fluorescence detection was developed for simultaneous quantitation of serotonin, fluoxetine and norfluoxetine in rat brain microdialysate. The column switching was configured such that position I of the switching valve employed column I (50 mm length) and column II (250 mm length) in series. This configuration resulted in optimal resolution of serotonin from interfering neurochemicals from rat brain. After elution of serotonin at 13.2 min the valve was switched to position II in which the flow of the mobile phase was directed through column I only. Flow gradient programming was then used to ramp the flow rate from 0.1 to 0.4 ml min-1 which resulted in optimal elution of fluoxetine and norfluoxetine. Strategic optimization of the single mobile phase enabled use of a single pump and detector making the analytical system simple and cost effective. Wavelength programmed fluorescence enabled sensitive detection of the analytes despite the difference in their fluorescence spectrum. The limit of detection for serotonin, norfluoxetine and fluoxetine were 10, 612 and 523 fmol, respectively. Rat brain microdialysate samples demonstrated selectivity for serotonin, fluoxetine and norfluoxetine. The method demonstrates application to the study of site specific neuropharmacokinetics and neuropharmacodynamics of fluoxetine in vivo.

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[A comparative clinical evaluation of the antidepressive activity of fluoxetine and fluvoxamine]

[Article in Russian]

Lopukhov IG.

Comparative study of the peculiarities of clinical action of fluoxetine and fluvoxamine in 65 patients with endogenous depressions revealed their high efficiency (in 74.3% and 64.3% respectively). Fluoxetine was characterised by predominance of a stimulating effect from the first days of treatment as well as by relatively late manifestation of very thymoleptic and tranquilizing impact (during 3-4 weeks). Fluvoxamin displayed relatively uniform occurrence of separate clinical effects together with predominance and early appearance of antidepressive influence. On the basis of the comparison of the peculiarities of either clinical action of fluoxetine and fluvoxamin or their side effects with those of traditional antidepressive drugs (amitryptilin and ludiomil) the preferable indications for their prescription were determined. Thus fluoxetine was very good in treatment of apathetic-adynamic depressions while fluvoxamin was recommended for therapy of anxious and melancholic depressions. Antidepressants studied were ranked in the following way in terms of decrease of sedative effect and increase of stimulating action: amitryptilin, fluvoxamin, ludiomil, fluoxetine. The proper thymoleptic effect of fluoxetine and fluvoxamin exceeded the same effect of amitryptilin and ludiomil.

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Long-term effects of fluoxetine or vehicle administration during pregnancy on behavioral outcomes in guinea pig offspring.

Vartazarmian R, Malik S, Baker GB, Boksa P.

Department of Psychiatry, Douglas Hospital Research Center, McGill University, 6875 LaSalle Boulevard, Verdun, QC, Canada, H4H 1R3, patricia.boksa mcgill.ca.

RATIONALE: Assessment of the benefits versus risks associated with antidepressant use during pregnancy must include an analysis of possible drug effects on fetal development. Human studies indicate that prenatal fluoxetine exposure is associated with adverse neonatal outcomes. Animal modeling may provide useful information concerning possible long-term effects of prenatal fluoxetine exposure. Limitations in previous such studies using rat models may be overcome using a guinea pig model in which fluoxetine is delivered by osmotic pump throughout pregnancy.METHODS: Initial experiments measured the half-life of fluoxetine and dosing required to achieve human therapeutic blood levels in the guinea pig. In subsequent experiments, guinea pigs received fluoxetine or vehicle via osmotic pump or no treatment throughout pregnancy. Outcome measures included: pregnancy characteristics, weight gain, and, in offspring as adults, pain threshold, acoustic startle responses and prepulse inhibition.RESULTS: There was no effect of treatment group on gestation length, number of live-births or still-births, maternal or offspring weight gain, and acoustic startle responses. In adult offspring, pain threshold was decreased by vehicle treatment during gestation. Prenatal fluoxetine increased pain threshold, relative to vehicle controls. Prepulse inhibition of startle was increased in adult offspring treated prenatally with either vehicle or fluoxetine compared to no treatment.CONCLUSIONS: The guinea pig provides a practicable and clinically relevant model of prenatal fluoxetine exposure. Adult guinea pigs exposed to fluoxetine prenatally showed increased thermal pain thresholds but no change in prepulse inhibition, indicating selective long-term effects of prenatal fluoxetine on serotonin-modulated behaviors. Further studies on long-term effects of prenatal fluoxetine on nociception are warranted.

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Inhibition of a 5-HT3 receptor-mediated current by the selective serotonin uptake inhibitor, fluoxetine.

Fan P.

Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852.

The effect of the selective serotonin uptake inhibitor, fluoxetine, on the inward current mediated by 5-HT3 receptors was investigated with the whole-cell patch-clamp technique. Fluoxetine inhibited the peak 5-HT current with an IC50 value of 1.2 microM. During continuous application of fluoxetine at concentrations of < or = 1 microM, there was a transient decrease in the fluoxetine-induced inhibition of 5-HT current. It is suggested that fluoxetine may have a short-lived action on 5-HT current and that the 5-HT3 receptor is a possible acting site for the therapeutic use of fluoxetine.

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Short-term fluoxetine treatment alters monoamine levels and turnover in discrete brain nuclei.

Frankfurt M, McKittrick CR, Luine VN.

Department of Neuroendocrinology, Rockefeller University, New York, NY 10021.

The effects of short-term fluoxetine administration on monoamine levels and turnover were assessed in discrete brain nuclei. Adult male rats received fluoxetine HCl (10 mg/kg) or saline injections intraperitoneally for 4 days and monoamine levels determined by high performance liquid chromatography. The major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), was decreased by fluoxetine treatment in the ventromedial hypothalamic nucleus (VMN), the lateral hypothalamic area and the CA1 region of the hippocampus. Fluoxetine treatment significantly increased serotonin (5-HT) levels in the VMN but did not change 5-HT levels in any other area examined. Norepinephrine (NE) levels were higher in fluoxetine-treated rats in the dorsomedial hypothalamic nucleus, dorsal raphe nucleus and parietal motor cortex (MCTX). 5-HT and NE turnover were also determined by the pargyline method. Fluoxetine treatment decreased 5-HT turnover in the VMN and increased 5-HT turnover in the median raphe. NE turnover was decreased in the preoptic area, the MCTX and parietal sensory cortex by fluoxetine administration. These results demonstrate that brain areas with similar 5-HT innervation respond differently to fluoxetine administration and fluoxetine, which selectively alters 5-HT uptake, also affects NE levels and turnover in several brain nuclei.

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Role of serotonin in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats.

Yan QS, Jobe PC, Cheong JH, Ko KH, Dailey JW.

Department of Basic Sciences, University of Illinois College of Medicine at Peoria 61656.

This study was designed to demonstrate a role of serotonin in the anticonvulsant effect of fluoxetine, a serotonin reuptake inhibitor, in genetically epilepsy-prone rats. When varied doses of 5-hydroxytryptophan (12.5, 25, 50 mg/kg) were administered i.p. along with a fixed dose of fluoxetine (15 mg/kg) to severe seizure genetically epilepsy-prone rats, the severity of audiogenic seizures was decreased dose-dependently, and the combination treatment also produced a marked potentiation of the anticonvulsant effect when compared with administration of either drug alone. Pretreatment of severe seizure genetically epilepsy-prone rats with p-chlorophenylalanine depleted brain serotonin and reduced the anticonvulsant effectiveness of fluoxetine. By using intracerebral microdialysis, the depletion of serotonin after p-chlorophenylalanine treatment was confirmed by measuring thalamic extracellular serotonin and 5-hydroxyindoleacetic acid concentrations during basal release and in response to a challenge dose of fluoxetine. We concluded that serotonergic transmission may be involved in the anticonvulsant effect of fluoxetine in severe seizure genetically epilepsy-prone rats.

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Effects of fluoxetine on basal and K(+)-induced tritium release from synaptosomes preloaded with [3H]serotonin.

Gobbi M, Crespi D, Mennini T.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Synaptosomes from rat brain cortex and spinal cord were preloaded with [3H]serotonin ([3H]5-HT), superfused and exposed to fluoxetine and/or 15 mM K+. In both regions 10 microM, but not 1 microM fluoxetine evoked a marked tritium overflow, about 2 min later than the immediate [3H]5-HT release induced by K+, and mainly (73%) due to the efflux of a tritiated metabolite of 5-HT, possibly [3H]5-hydroxy-indoleacetic acid. These findings confirm previous data in the rat hippocampus and are probably due to fluoxetine interacting with the 5-HT storage vesicles. One microM fluoxetine significantly reduced the d-fenfluramine-induced [3H]5-HT overflow, in accordance with its action as 5-HT uptake blocker, but did not affect the K(+)-induced [3H]5-HT overflow. This latter finding does not confirm that fluoxetine inhibits the depolarization-induced Ca(2+)-influx, suggested to involve a drug interaction with the L-type Ca(2+)-channels. Thus, the overflow induced by 10 microM fluoxetine was additive with the depolarization-induced overflow, when the two stimuli were applied together. When 10 microM fluoxetine was added 7 min before 15 mM K+, there was no depolarization-induced overflow. Such inhibition might be only apparent and due either to the fluoxetine-induced loss of vesicular 5-HT or to a fluoxetine-induced alterations of synaptic vesicles. The in vivo relevance of the fluoxetine releasing effect remains to be assessed.

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Acute and chronic effects of fluoxetine and haloperidol on mouse brain serotonin and norepinephrine turnover.

Hall LM, Anderson GM, Cohen DJ.

Child Study Center, Yale University School of Medicine, New Haven, CT 06520-7900, USA.

Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In limited previous neurochemical research, acute treatment with selective serotonin reuptake inhibitors (SSRIs) has been reported to increase rat brain norepinephrine (NE) turnover or release. We have examined the neurochemical effects of 2 hr, 4 day, and 20 day treatment with the SSRI fluoxetine, and the neuroleptic haloperidol, on regional brain monoamine metabolism. Short and long-term fluoxetine treatment produced substantial decreases (to 65-79% of control) in serotonin (5HT) turnover. However no effects of fluoxetine on mouse brain NE turnover--as assessed by forebrain, hypothalamus, and hindbrain 3-methoxy-4-hydroxyphenylglycol (MHPG) levels or MHPG/NE ratios--were observed. Acute (2 hr) fluoxetine also did not alter regional NE turnover in rat brain. In contrast, haloperidol tended to increase MHPG levels and MHPG/NE ratios in the mouse brain regions studied. The persistence of decreased 5HT turnover during fluoxetine treatment, the lack of an effect of fluoxetine on NE turnover, and the increased NE turnover seen after haloperidol may have important implications regarding drug responsivity and the mechanism of akathisia induction.

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