citalopram Celexa
5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram.

Arborelius L, Nomikos GG, Grillner P, Hertel P, Hook BB, Hacksell U, Svensson TH.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT1A receptor antagonists, [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl-propionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)-WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.). We have also studied the effects of (S)-UH-301 (0.03-0.50 mg/kg i.v.) on the firing rate of single DRN-5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. x 14 days). Administration of (S)-UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 ml/kg/day i.p. x 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
The anticonvulsant effect of citalopram on El mice, and the levels of tryptophan and tyrosine and their metabolites in the brain.

Kabuto H, Yokoi I, Takei M, Kurimoto T, Mori A.

Department of Neuroscience, Okayama University Medical School, Japan.

Serotonin(5-HT) plays an important role in the seizures of El mice since the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by oral administration of citalopram for 2 weeks. Citalopram increased tryptophan and tyrosine amounts, and decreased the 5-HT, 5-hydroxyindoleacetic acid, kynurenine, and dopamine amounts in the brain. These findings show that citalopram depresses monoaminergic metabolism. Given the known convulsant effect of kynurenine, it is suggested that its decrease by citalopram may involve attenuation of El mice seizures.

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citalopram Celexa
Chronic administration of citalopram inhibited El mouse convulsions and decreased monoamine oxidase-A activity.

Kabuto H, Yokoi I, Endo A, Takei M, Kurimoto T, Mori A.

Department of Neuroscience, Okayama University Medical School, Japan.

Serotonin (5-HT) is thought to play an important role in the seizures of El mice because the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by chronic administration of citalopram (80 mg/kg/day, p.o. for 2 weeks), but were not inhibited by acute administration of citalopram (80 mg/kg, i.p., 2 h after single injection). Both chronic and acute administration of citalopram decreased the concentration of 5-hydroxyindolacetic acid in the brain, whereas the concentration of 5-HT was not changed by treatment with citalopram. Tryptophan hydroxylase activity was not different between the citalopram and control groups, although the monoamine oxydase-A activity was lowered by chronic administration of citalopram. These findings suggest that both acute and chronic administration of citalopram depresses the 5-HT turnover rate, however chronic administration is necessary to inhibit El mouse convulsions.

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citalopram Celexa
Citalopram, a serotonin reuptake inhibitor, and brain ischemia in SHR.

Nagao T, Ibayashi S, Sadoshima S, Izumi J, Fujishima M.

Second Department of Internal Medicine, Kyushu University, Fukuoka, Japan.

The effects of citalopram, a serotonin (5-HT) reuptake inhibitor, on cerebral blood flow (CBF) and concentration of 5-HT and its metabolite were investigated in spontaneously hypertensives rats (SHR) subjected to forebrain ischemia. Cerebral ischemia was induced by bilateral carotid artery occlusion. The concentration of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), increased during cerebral ischemia in most brain regions examined, while that of 5-HT increased only in the frontal cortex and the striatum. Citalopram restored the 5-HIAA concentrations to the preischemic normal levels. Citalopram had no effect on the cortical CBF, before and during ischemia. These results suggest that citalopram attenuates ischemia-induced hypermetabolism of 5-HT in the brain. The effects of citalopram are independent of hemodynamic factors including cerebral blood flow, and are likely to be mediated by a direct inhibition of the neuronal 5-HT reuptake system.

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citalopram Celexa
Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC.

Rochat B, Amey M, Van Gelderen H, Testa B, Baumann P.

Departement Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland.

A stereoselective HPLC assay has been developed to analyze the enantiomers of citalopram and of its three main metabolites in plasma after their separation on a Chiracel OD column. Using a fluorescence detector, the limit of quantification in plasma samples was 15, 4, 5 and 2 ng/ml for the enantiomers of citalopram (CIT), desmethylcitalopram (DCIT), didesmethylcitalopram (DDCIT), and for the citalopram propionic acid derivative (CIT-PROP), respectively. Except for CIT, all metabolites were derivatized with achiral reagents. Identification of the enantiomers was realized with an optical rotation detector which showed that the enantiomers invert their rotation depending on the polarity and nature of the solvent. Under varying conditions, a racemization study has shown that the pure enantiomers of CIT and its demethylated metabolites are configurationally stable. Preliminary results obtained with five patients treated with CIT show a mean S/R ratio of 0.7 for both CIT and its active metabolite DCIT and of 3.6 for CIT-PROP in plasma. This suggests that the pharmacologically relevant (+)-(S)-isomers of CIT and DCIT could be preferentially and stereoselectively metabolized to CIT-PROP.

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citalopram Celexa
Simultaneous determination of citalopram and its metabolites by high-performance liquid chromatography with column switching and fluorescence detection by direct plasma injection.

Matsui E, Hoshino M, Matsui A, Okahira A.

Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.

High-performance liquid chromatography with a successive column-switching technique was developed for simultaneous determination of citalopram and its four metabolites in plasma. Plasma samples were injected directly, and the target compounds were purified and concentrated with an inexpensive commercial octadecyl guard column. Then, the six-port valve was switched, and the compounds retained in the column were eluted by the back-flush method using 20 mM phosphate buffer (pH 4.6)-acetonitrile (70:30, v/v) containing 0.1% diethylamine and separated with an ODS column. The compounds were assayed with a fluorescence detector at an excitation wavelength of 249 nm and an emission wavelength of 302 nm. At least 30 plasma samples could be treated with an octadecyl guard column. The limits of quantitation of this method were 2.0 ng/ml for citalopram, desmethylcitalopram, didesmethylcitalopram, citalopram propionic acid and citalopram N-oxide. This method was applied to a pharmacokinetic study in dogs and a toxicokinetic study in rats.

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citalopram Celexa
Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography.

Rochat B, Amey M, Baumann P.

Unite de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland.

A stereospecific high-performance liquid chromatography (HPLC) method has been developed for the analysis of the underived enantiomers of citalopram (CIT) and its N-demethylated metabolites in plasma. Using fluorescence detection, the limit of quantification for each enantiomer is 3 ng/ml. CIT N-oxide and the CIT propionic acid derivative are not extracted by the procedure used. Inter- and intraday validations of the method using reverse-phase mode HPLC on separate acetylated beta-cyclobond columns showed the sensitivity of this assay to be suitable for pharmacokinetic studies of the enantiomers of these compounds. Plasma levels of the enantiomers and the demethylated metabolites of CIT have been determined during routine therapeutic drug monitoring (TDM) in 29 depressive patients treated with varying dosages (20-80 mg/day) of CIT. Concentrations of S-(+)-CIT, which is considered the most potent selective serotonin reuptake inhibitors (SSRI) of the CIT and desmethylcitalopram (DCIT) enantiomers, varied between 24-49% (mean +/- sd, 35% +/- 5%) of the concentrations of total CIT. There were highly significant correlations between S-(+)-CIT and R-(-)-CIT levels (r = 0.866; p < 0.0001) and between S-(+)-DCIT and R-(-)-CIT (r = 0.932; p < 0.0001). The co-medications seemed to have little influence on enantiomer ratios. These results suggest the need for studies on the relationships between clinical response and plasma levels of CIT enantiomers.

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citalopram Celexa
The presence of a serotonin uptake inhibitor alters pharmacological manipulations of serotonin release.

Kreiss DS, Wieland S, Lucki I.

Institute of Neurological Sciences, University of Pennsylvania, Philadelphia 19104.

The present study investigated the effects of the presence of the serotonin uptake inhibitor citalopram in the perfusion medium on pharmacological manipulations which increased and decreased striatal serotonin release using in vivo microdialysis. A high performance liquid chromatography detection system equipped with a microbore column was used which reduced the detection limit to 0.5 fmol serotonin/5 microliters sample and enabled basal striatal serotonin release to be measured without the addition of a serotonin uptake inhibitor to the perfusion medium. Although serotonin uptake inhibitors have frequently been used to enhance the serotonin content of dialysate samples, the effects of the presence of serotonin uptake inhibitors on pharmacological manipulations which increased and decreased the release of serotonin have not yet been characterized. Serotonin release was reduced by the systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Although 5-HT release was reduced by 8-OH-DPAT after the addition of citalopram, the 5-HT1A receptor agonist did not reduce absolute levels of extracellular serotonin below basal values of serotonin measured in the absence of citalopram. In addition, citalopram dramatically prevented the four-fold increase in the release of serotonin produced by the systemic administration of the serotonin-releasing agent fenfluramine. The blockade of fenfluramine's effects by citalopram supports the hypothesis that transport of fenfluramine into serotonergic neurons is necessary to increase serotonin release. This study demonstrates that the use of an HPLC detection system equipped with a microbore column can reliably measure basal serotonin release using in vivo microdialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

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