citalopram escitalopram Lexapro
Binding of pinoline on the 5-hydroxytryptamine transporter: competitive interaction with [3H] citalopram.

Pahkla R, Rago L, Callaway JJ, Airaksinen MM.

Department of Pharmacology, University of Tartu, Estonia.

Pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) is a naturally occurring compound in the mammalian body which inhibits 5-hydroxytryptamine (5-HT) uptake and exerts antidepressant-like behavioural effects in rats. The present study investigates the effects of pinoline on [3H]citalopram binding to the 5-HT transporter on rat brain. Our experiments revealed that pinoline inhibits [3H]citalopram binding with IC50 1255 +/- 167 nM and Ki 572 +/- 76 nM; Hill coefficient for inhibition was close to 1. In saturation experiments, pinoline co-incubated with [3H]citalopram, increased dose-dependently the Kd value but had no effect on the Bmax value of [3H]citalopram binding. Micromolar concentrations of pinoline did not have influence on the dissociation rate of specifically bound [3H]citalopram. Binding parameters of [3H]citalopram did not differ significantly in cerebral cortex and hippocampus of rats treated for 10 days with pinoline or vehicle. These results indicate that pinoline did not have any modulative influence on the activity of 5-HT transporter and it interacts competitively with citalopram on the substrate recognition site of the 5-HT transporter.

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citalopram escitalopram Lexapro
Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes.

Rochat B, Amey M, Gillet M, Meyer UA, Baumann P.

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

Using in vitro techniques, the present study demonstrates that CYP2D6, and 3A4 are involved in N-demethylation of citalopram (CIT) enantiomers. Human liver microsome incubations performed with specific inhibitors of these three CYP isozymes have shown up to 60% inhibition of demethylcitalopram production. cDNA expressed human cytochrome P-450 3A4, 2C19 and 2D6 isozymes, but not CYP1A2, were identified to be involved in N-demethylation of CIT enantiomers. Kinetics using cDNA expressed CYP2C19 and CYP3A4 show K(m) values in the same range: 198 microM, 211 microM for CYP2C19 and 169 microM, 163 microM for CYP3A4 for S- and R-CIT demethylation, respectively. In contrast, kinetics using cDNA expressed CYP 2D6 show a K(m) of 18 microM and 22 microM for S- and R-CIT demethylation, respectively. Nevertheless, kinetics using cDNA expressed CYP2C19 and 3A4 have a range of Vmax values ten times higher than that of CYP2D6. For this reason, intrinsic clearance values (Vmax/K(m)) for S- and R-CIT were within a small range for these three isozymes: 0.25 to 0.39 microliter h-1 x pmol-1 of CYP. CYP2D6 has an opposite stereoselectivity in the biotransformation of CIT enantiomers than CYP2C19 and 3A4; the S/R ratios of the intrinsic clearance were 0.71, 1.57 and 1.37, respectively. Taking into account that CYP isozymes are expressed at various levels, CYP2D6, which is expressed at lower levels than CYP2C19 and CYP3A4, plays a minor role in the biotransformation of CIT enantiomers. These results confirm that the use of cDNA expressed CYP isozymes is a potent tool for the measurement of kinetic constants and help to predict clearance modifications of CIT enantiomers, especially in poor metabolizers of mephenytoin (with a CYP2C19 deficiency) or patients comedicated with potent CYP2C19 or 3A4 inhibitor(s). For instance, fluvoxamine (100 microM) inhibits CIT N-demethylation by 64% in microsomes.

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citalopram escitalopram Lexapro
Effects of adrenalectomy and corticosterone replacement on diurnal [3H]citalopram binding in rat midbrain.

Kulikov A, Mormede P, Chaouloff F.

INSERM CJF 94-05, INRA, Institut F. Magendie, Bordeaux, France.

Corticosteroids modulate the expression and/or functions of several serotonin (5-hydroxytryptamine; 5-HT) receptors. Conversely, analyses of the effects of corticosteroids upon 5-HT reuptake systems have been scarce and contradictory. Herein, the diurnal rhythm of midbrain [3H]citalopram binding to 5-HT transporters was analysed in sham and 11 day adrenalectomised rats. In addition, adrenalectomised rats were either complemented or not with corticosterone pellets (12.5-200 mg). Analyses of body weight increases and plasma adrenocorticotropic and corticosterone levels indicated that the protocol allowed the stimulation of mineralocorticoid receptors (MRs; 12.5 mg pellets) or the stimulation of both MRs and glucocorticoid receptors (GRs; 50-200 mg pellets). However, besides the observation of a slight, but significant diurnal (corticosteroid-independent) rhythm in 5-HT transporter binding (morning > evening), it was found that neither adrenalectomy nor corticosteroid receptor stimulation affected midbrain [3H]citalopram binding.

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citalopram escitalopram Lexapro
The effect of combined administration of ethanol and sertraline, fluoxetine and citalopram on rabbit EEG.

Pietrzak B, Czarnecka E.

Department of Pharmacodynamics, Medical University of Lodz, Muszynskiego 1, 90-151, Lodz, Poland. bpietrzak pharm.am.lodz.pl

In this study we have decided to examine acute interaction of ethanol with some drugs that belong to selective serotonin inhibitor (SSRI) group. Therefore, the influence of sertraline, fluoxetine and citalopram on the effect of ethanol on EEG of rabbits (frontal cortex, hippocampus, MRF) was tested. Sertraline (10mg/kg i.p.), fluoxetine (10mg/kg i.p.) and citalopram (5mg/kg i.p.) were given 30min before ethanol injection in a dose 0.8g/kg i.v. Ethanol caused the increase of the slow frequencies (0.5-4cps) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45cps). Sertraline, fluoxetine and citalopram (given before ethanol) prevented the increase in the slow frequencies (0.5-4cps) in the recordings from the frontal cortex and hippocampus, which indicates on antagonism inhibitory action of ethanol. These drugs administered together with ethanol may increase its influence on fast frequencies. This effect depends on brain structure and drug.

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citalopram escitalopram Lexapro
The effects of cholecystokinin A and B receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in rat.

Matto V, Harro J, Allikmets L.

Department of Pharmacology, University of Tartu, Estonia.

The present study has been divided into two sets. In the first set, the aim of the experiments was to investigate the dose-response effect of selective serotonin re-uptake inhibitor (SSRI) citalopram on rat exploratory behaviour in the elevated plus-maze. In the second set of experiments, the effect of cholecystokinin (CCK) CCKA and CCKB receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in the elevated plus-maze was studied. Citalopram (5 and 10 mg/kg) decreased the number of open and total arm entries, line crossings on open arms, and percentage of time spent exploring in open arm. Dose 15 mg/kg was without any effect on rat exploratory behaviour. Devazepide (0.01 and 1.0 mg/kg) failed to modify any of the citalopram-induced changes observed. L 365260 (1.0 mg/kg) reversed most of the effects of citalopram: the numbers of open and total arm entries, the number of line crossings, and the percentage of time spent exploring in open arms. L 365260 at dose level 0.01 mg/kg was ineffective. These results support the involvement of the CCKB receptor subtype in SSRI-induced anxiogenic-like effects in rodents.

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citalopram escitalopram Lexapro
Effects of a chronic lithium treatment on cortical serotonin uptake sites and 5-HT1A receptors.

Carli M, Afkhami-Dastjerdian S, Reader TA.

Centre de Recherche en Sciences Neurologiques, Faculte de Medecine, Universite de Montreal, Quebec, Canada.

The objectives of this study were to characterize the effects of a chronic lithium (Li+) treatment on serotonin (5-HT) uptake sites and on 5-HT1A receptors, and to determine the eventual reversibility of the treatment. The experiments were carried out with membranes from rat cerebral cortex using 8-hydroxy-2-(propylamino)tetralin, or [3H]8-OH-DPAT, and [3H]citalopram to label 5-HT1A receptors and 5-HT uptake sites, respectively. Endogenous levels of 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography in the cingulate cortex. The saturation curves with [3H]8-OH-DPAT were always best fitted a two-site model. After a treatment with Li+ for 28 days, no alterations in the binding parameters of [3H]8-OH-DPAT to the high- and low-affinity binding sites could be documented. However, competition curves with 5-HT to inhibit [3H]8-OH-DPAT binding revealed a decreased proportion of sites with high affinity for the agonist, together with an increased density of sites with low affinity for 5-HT, suggesting an alteration in the coupling efficacy between 5-HT1A receptors and their transduction systems. Saturation studies with [3H]citalopram showed an increase (> 40%) in the density of 5-HT uptake sites after chronic Li+, suggesting a more efficient 5-HT uptake process for the treated animals, in accord with clinical observations. Although 5-HT contents in cingulate cortex remained unchanged after the treatment, 5-H[AA levels decreased (> 30%), leading to a diminished (almost 50%) 5-HT turnover; and also reflecting a more efficient uptake in the treated rats, so that less 5-HT could be degraded by extracellular monoamine oxidase. All the effects revealed by [3H]8-OH-DPAT and [3H]citalopram were reversed following a recovery period of two days without Li+. Since symptoms of bipolar affective disorders may reappear if the chronic Li+ treatment is interrupted, the reversibility of the observed effects further supports the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective disorders.

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citalopram escitalopram Lexapro
An affinity-modulating site on neuronal monoamine transport proteins.

Plenge P, Mellerup ET.

Department of Pharmacology, University of Copenhagen, Rigshospitalet-6102, Denmark.

The dissociation rates of [3H]nisoxetine, [3H]GBR 12935 and [3H]citalopram from, respectively, the rat brain noradrenaline, dopamine and 5-HT transporters were found to be markedly affected by several drugs. Sertraline strongly attenuated the rate of dissociation of [3H]nisoxetine from the noradrenaline transporter, while citalopram strongly attenuated that of [3H]citalopram from the 5-HT transporter. The effect of both drugs were stereospecific. Less potent affinity-modulating drugs were identified with regards to [3H]GBR 12935 dissociation from the dopamine transporter. All three neuronal monoamine transporters may thus have specific affinity-modulating sites which change the function of the transporters with possible implication for the reuptake of monoamines released during synaptic activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140140&dopt=Abstract citalopram escitalopram Lexapro