citalopram Celexa
Serotonin reuptake inhibition by citalopram in rat strains differing for their emotionality.

Pollier F, Sarre S, Aguerre S, Ebinger G, Mormede P, Michotte Y, Chaouloff F.

Laboratory of NeuroGenetique and Stress, INSERM U471, Bordeaux, France.

Acute administration of the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram (1-10 mg/kg, i.p. 1 h before an elevated plus-maze test), to Spontaneously Hypertensive rats (SHRs), Lewis (LEW) rats, and Wistar-Kyoto (WKY) rats, i.e., rat strains differing for their emotionality, promoted anxiety, and/or hypoactivity, except in WKY rats. In the three strains, such a pretreatment increased central 5-HT levels and/or decreased 5-hydroxyindoleacetic acid levels. Hippocampal, but not midbrain or striatal, [3H]citalopram binding at 5-HT transporters was lower in WKY rats than in SHRs. However, neither [3H]5-HT reuptake kinetics nor the potencies of citalopram (1-1000 nM) to inhibit [3H]5-HT reuptake into hippocampal and striatal synaptosomes differed between strains. This was confirmed in vivo by means of microdialysis in the hippocampus of freely moving rats. Thus, although LEW rats displayed a 3-4 fold higher baseline level of extracellular 5-HT in the hippocampus, compared with SHRs and WKY rats, local perfusion with 1 microM citalopram promoted relative increases in extracellular 5-HT levels over baseline that were similar in all strains. Lastly, acute i.p. administration of 3.3 mg/kg citalopram (1 h beforehand) decreased to similar extents [3H]5-HT reuptake into hippocampal synaptosomes from SHRs and WKY rats. This study indicates that genetic differences in the behavioural responses to SSRIs may involve 5-HT transporter-independent mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10633492&dopt=Abstract citalopram Celexa



citalopram Celexa
Antidepressant-like effects in various mice strains in the tail suspension test.

Ripoll N, David DJ, Dailly E, Hascoet M, Bourin M.

Faculte de Medecine, EA 3256 Neurobiologie de l'anxiete et de la depression, BP 53508, 1 rue Gaston Veil, F44035 Nantes, Cedex 01, France.

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion.The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12900045&dopt=Abstract citalopram Celexa



citalopram Celexa
The activity of rat brain nitric oxide synthase following chronic antidepressant treatment.

Jopek R, Kata M, Nowak G.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Nitric oxide synthase (NOS) is an enzyme involved in the activation of the glutamate/NMDA receptor-induced cascade of events. In this study we investigated the NOS activity in different rat brain regions after chronic electroconvulsive, imipramine and citalopram treatments. Chronic electroconvulsive treatment significantly increased the NOS activity (by 49%) in the cerebral cortex. However, chronic treatment with imipramine or citalopram did not alter the activity of NOS in all examined brain regions (cortex, hippocampus or cerebellum). The increased NOS activity after electroconvulsive but not pharmacologic (imipramine or citalopram) treatment may well reflect the differences between the adaptive changes of the NMDA receptor complex induced by these treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10635364&dopt=Abstract citalopram Celexa



citalopram Celexa
Enantiomeric separation of citalopram and its metabolites by capillary electrophoresis.

Mandrioli R, Fanali S, Pucci V, Raggi MA.

Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.

A simple and fast capillary electrophoretic method has been developed for the enantioselective separation of citalopram and its main metabolites, namely N-desmethylcitalopram and N,N-didesmethylcitalopram, using beta-cyclodextrin (beta-CD) sulfate as the chiral selector. For method optimisation several parameters were investigated, such as CD and buffer concentration, buffer pH, and capillary temperature. Baseline enantioseparation of the racemic compounds was achieved in less than 6 min using a fused-silica capillary, filled with a background electrolyte consisting of a 35 mM phosphate buffer at pH 2.5 supplemented with 1% w/v beta-CD sulfate and 0.05% w/v beta-CD at 25 degrees C and applying a voltage of -20 kV. A fast separation method for citalopram was also optimized and applied to the analysis of pharmaceutical formulations. Racemic citalopram was resolved in its enantiomers in less than 1.5 min using short-end injection (8.5 cm, effective length) running the experiments in a background electrolyte composed of a 25 mM citrate buffer at pH 5.5 and 0.04% w/v beta-CD sulfate at a temperature of 10 degrees C.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12900873&dopt=Abstract citalopram Celexa



citalopram Celexa
Extracellular concentrations of serotonin in the dorsal hippocampus after acute and chronic treatment with citalopram.

Invernizzi R, Bramante M, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Citalopram, 1 and 10 mg/kg i.p., that in a previous study using identical treatment and dialysis conditions had little or no effect on dialysate serotonin (5-HT) in the frontal cortex, dose-dependently raised the extracellular concentrations of 5-HT in the dorsal hippocampus, by 70% and 205% respectively at the peak. In animals given 10 mg/kg citalopram twice daily for 14 days, intraperitoneal doses of 1 and 10 mg/kg or infusion of 10(-8) - 10(-6) M through the hippocampal probe raised dialysate 5-HT in the dorsal hippocampus similarly in animals treated chronically with citalopram or saline. A dose of 100 micrograms/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist at 5-HT1A receptors, reduced hippocampal extracellular 5-HT concentrations to the same extent in rats repeatedly given saline or citalopram. Half this dose had no such effect in either group. The effect of citalopram and the sensitivity of autoreceptors controlling 5-HT release in the dorsal hippocampus were unaffected by a chronic treatment known to facilitate the drug's effect on dialysate 5-HT and to reduce the sensitivity of 5-HT1A receptors controlling 5-HT release in the frontal cortex. The effects of acute and chronic treatment with citalopram on dialysate 5-HT in the rat brain thus appear to differ in at least two brain regions: the frontal cortex and the dorsal hippocampus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8574685&dopt=Abstract citalopram Celexa



citalopram Celexa
Effects of haloperidol, clozapine and citalopram on messenger RNA levels of chromogranins A and B and secretogranin II in various regions of rat brain.

Kroesen S, Marksteiner J, Mahata SK, Mahata M, Fischer-Colbrie R, Saria A, Kapeller I, Winkler H.

Department of Pharmacology, University of Innsbruck, Austria.

We have measured the messenger RNA levels of chromogranins A and B and secretogranin II in various brain regions of rats subchronically treated with various antipsychotic drugs. Since, as shown previously, the messenger RNA levels of these peptides are increased when neurons are stimulated, we hoped to identify by this approach those nuclei which are subchronically influenced by these drugs. The drugs chosen were the neuroleptic halperidol, a blocker of dopamine receptors, the atypical antipsychotic clozapine, which in addition to blocking dopamine receptors also blocks those for serotonin, and citalopram, a specific serotonin reuptake inhibitor. In agreement with previous data on neuropeptide messenger RNAs, we found in the dorsolateral striatum an increase of the secretogranin II messenger RNA levels after haloperidol and a much smaller one after clozapine. In the nucleus accumbens and in the bed nucleus of the stria terminalis, both compounds had a comparable positive effect. These differential effects can be attributed to a different action of these drugs on dopamine receptor subtypes. In the zona incerta, clozapine decreased the secretogranin II and chromogranin A message, whereas in the dorsal raphe it led to an increase. On the other hand, citalopram induced exactly the opposite effects in these two brain regions. This phenomenon can be explained by the differential interaction of these drugs with serotonergic mechanisms. Additional, relatively small changes of the mRNAs were seen in several other brain regions. These results establish that changes in the mRNA levels of the chromogranins are good indicators for the effect of drugs on certain brain nuclei. The concomitant action of haloperidol and clozapine on the limbic regions, i.e. the nucleus accumbens and the bed nucleus of the stria terminalis, points to these brain regions for the antipsychotic action of these two neuroleptics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8596656&dopt=Abstract citalopram Celexa



citalopram Celexa
Simplified high-performance liquid chromatographic method for the determination of citalopram and desmethylcitalopram in serum without interference from commonly used psychotropic drugs and their metabolites.

Olesen OV, Linnet K.

Department of Biological Psychiatry, Psychiatric Hospital, Aarhus University Hospital, Risskov, Denmark.

A simplified method for the determination of racemic citalopram and its main metabolite desmethylcitalopram in serum using HPLC was developed. The compounds were extracted with heptane-isoamyl alcohol (98:2) and subsequently transferred into phosphate buffer pH 2.5 for direct injection into the HPLC apparatus. The analytes were separated with an acetonitrile-phosphate buffer, pH 2.5-tetraethylamine mobile phase on a C18 column and measured by UV detection at 240 nm. Within the typical range of serum concentrations (30-100 ng/ml) the inter-day variation was < 6% for both compounds. Possible analytical interference from a number of commonly coadministered psychoactive drugs and their metabolites was studied by extracting sera from patients receiving these drugs. Interference was not a problem for the developed method.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8634772&dopt=Abstract citalopram Celexa



citalopram Celexa
Pharmacological characterization of the cloned human 5-hydroxytryptamine transporter.

Agnel M, Esnaud H, Langer SZ, Graham D.

Synthelabo Recherche, Rueil Malmaison, France.

We performed an extensive pharmacological study of the 5-hydroxytryptamine (5-HT) transporter polypeptide cloned from human placenta. Transient expression of this 630 amino acid polypeptide in HeLa cells led to saturable 5-HT uptake activity (Km = 858 nM). This 5-HT uptake was blocked by selective 5-HT inhibitors, such as citalopram, litoxetine, sertraline, and indalpine, with Ki values in the low nanomolar range, and it exhibited a pharmacological profile similar to that found in rat brain. [3H]Citalopram binding to membrane preparations of the transfected cells occurred to a single class of high-affinity binding sites (Kd = 5.3 nM) and was potently inhibited by selective 5-HT uptake inhibitors. The pharmacological profile of [3H]citalopram binding to these transfected cells showed a good correlation with that of [3H]paroxetine binding to the rat cerebral cortical 5-HT transporter (r = 0.79). These data confirm that the full pharmacological characteristics of the 5-HT transport system are conferred by the expression of the 630 amino acid human placental 5-HT transporter polypeptide. [3H]Citalopram should, therefore, provide a useful probe for more insights at a molecular level into this cloned 5-HT transport system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8645336&dopt=Abstract citalopram Celexa