citalopram escitalopram Lexapro
Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing.

Inoue T, Hashimoto S, Tsuchiya K, Izumi T, Ohmori T, Koyama T.

Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.

The present study examined the effects of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor citalopram on the acquisition of conditioned freezing, an index of anxiety. Acute treatment with citalopram (1-10 mg/kg) dose dependently prevented the acquisition of conditioned freezing, while acute treatment with noradrenaline or dopamine reuptake inhibitors failed. The acute effect of citalopram was not antagonized by the 5-HT1A receptor antagonist NAN190, 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl]piperazine or the 5-HT2A/2C receptor antagonist ICI169,369, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride. These results indicate that selective 5-HT reuptake inhibitors reduce not only the expression of conditioned freezing as reported previously, but also the acquisition of conditioned freezing. Both these effects of selective 5-HT reuptake inhibitors may be related to their clinical efficacy in the treatment of anxiety disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8884229&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites.

Bennett-Clarke CA, Chiaia NL, Rhoades RW.

Dept. of Anatomy and Neurobiology, Medical College of Ohio, Toledo 43699, USA.

Autoradiographic techniques using [3H]citalopram were employed in 8-day-old (P-8) and adult rats to delineate the distribution of high-affinity serotonin (5-HT) uptake sites in the cerebral cortex. In the postnatal rats, [3H]citalopram binding sites were densely distributed in the lower portion of layer III, lamina IV, and upper layer V in the primary visual, somatosensory, and auditory cortices. In the primary somatosensory cortex, these binding sites were arrayed in a manner exactly matching the representation of the body surface as demonstrated by other methods such as staining for cytochrome oxidase (CO) or acetylcholinesterase (AChE). In adult rats, there was no differential distribution of [3H]citalopram binding sites in the cerebral cortex. Neonatal administration of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), resulted in a nearly complete destruction of the 5-HT innervation of the cortex on P-8, but the patterned distribution of [3H]citalopram binding sites remained visible. In contrast, thalamic lesions carried out on P-4 caused a complete loss of the patterned distribution of [3H]citalopram binding sites in rats killed on either P-5 or P-8. These results are consistent with the conclusion that thalamocortical afferents in postnatal rats transiently express high-affinity uptake sites for 5-HT and thus may accumulate this amine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8891315&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities.

Sanchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A, Wiborg O.

Research Laboratories, H. Lundbeck A/S, Ottiliavej 9, 2500 Copenhagen, Denmark. cs lundbeck.com

OBJECTIVE: The pharmacological profile of escitalopram, the S-(+)-enantiomer of citalopram, was studied and compared with citalopram and the R-(-)-enantiomer, R-citalopram. METHODS: Inhibition of the serotonin transporter (5-HTT) was studied in COS-1 cells expressing the human 5-HTT (h-5-HTT) and in rat brain synaptosomes. In vitro selectivity was studied relative to noradrenaline transporter (NAT) and dopamine transporter (DAT) function in rat brain synaptosomes, and affinities for other binding sites were determined. In vivo 5-HT activity was measured as inhibition of neuronal firing rate in rat dorsal raphe nucleus (DRN) and enhancement of 5-hydroxytryptophan (5-HTP)-induced behaviour (mouse and rat). Furthermore, studies were conducted in models of antidepressant (mouse forced-swim test), anxiolytic [foot-shock-induced ultrasonic vocalization (USV) in adult rats and mouse black and white box] and anti-aggressive activity (socially isolated mice). RESULTS: Escitalopram inhibited 5-HTT functions approximately 2 times more potently than citalopram and at least 40 times more potently than R-citalopram. Escitalopram showed insignificant activity at other monoamine transporters and 144 other binding sites. Escitalopram inhibited 5-HT neuronal firing in DRN and potentiated 5-HTP-induced behaviours more potently than citalopram; R-citalopram was inactive. Escitalopram and citalopram, but not R-citalopram, reduced forced-swimming-induced immobility and facilitated exploratory behaviour in the black and white box. Escitalopram and citalopram inhibited USV potently; R-citalopram was several times less potent. Escitalopram, citalopram and R-citalopram inhibited aggressive behaviour weakly. Escitalopram and citalopram had very potent anti-aggressive effects when co-administered with l-5-HTP. CONCLUSION: Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12719960&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Adaptation of cortical but not hippocampal NMDA receptors after chronic citalopram treatment.

Nowak G, Li Y, Paul IA.

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216-4505, USA.

Chronic treatment with citalopram produced a 6.2-fold reduction in the proportion of high affinity glycine-displaceable [3H]CGP-39653 binding sites and a 1.5-fold reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding in mouse cortex but not in hippocampus. Chronic citalopram also increased the aspartate concentration by 110% in cortex and 33% in hippocampus, and increased the glycine/threonine concentration by 33% in hippocampus. These results support the hypotheses that: (1) the adaptation of strychnine-insensitive glycine recognition sites and the allosteric coupling of the glycine and glutamate recognition sites are independently regulated by chronic antidepressant treatment; (2) chronic antidepressant administration induces regionally selective adaptation of the NMDA receptor complex; and (3) antidepressant-induced adaptation of the NMDA receptor complex may be mediated by regionally selective changes in excitatory amino acid concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8925878&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Blockade of serotonin 5-HT1B and 5-HT2A receptors suppresses the induction of locomotor activity by 5-HT reuptake inhibitors, citalopram and fluvoxamine, in NMRI mice exposed to a novel environment: a comparison to other 5-HT receptor subtypes.

Millan MJ, Veiga S, Girardon S, Brocco M.

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 Chemin de Ronde, 78290 Croissy/Seine, France. mark.millan fr.netgrs.com

RATIONALE: Though 5-HT plays an important role in the modulation of motor function, which is perturbed in depressive states, little is known concerning the influence of serotonin reuptake inhibitors (SSRIs) on locomotor activity (LA). Recently, we demonstrated that SSRIs, such as citalopram, enhance LA in mice exposed to a novel environment. OBJECTIVES: This study examined the role of multiple classes of 5-HT receptor in citalopram-induced LA. METHODS: The most selective antagonists currently available were used. RESULTS: Citalopram-induced LA was dose-dependently attenuated by the 5-HT1B/1D receptor antagonists, S18127, GR125,743 and GR127,935, and by the selective 5-HT1B antagonist, SB224,289, but unaffected by the selective 5-HT1A antagonist, WAY100,635. The selective antagonists at 5-HT2A receptors, MDL100,907 and SR46,349 also dose-dependently attenuated induction of locomotion by citalopram, whereas the 5-HT2B antagonist, SB204,741, and the 5-HT2B/2C antagonist, SB206,553 were ineffective. Further, the selective 5-HT2C antagonist, SB242,084, potentiated the response to citalopram. Selective antagonists at 5-HT3 (ondansetron), 5-HT4 (GR125,487), 5-HT6 (SB271,046) and 5-HT7 (SB269,970) receptors did not significantly modify the action of citalopram. Underpinning these findings, SB224,289, GR125,743, MDL100,907 and SR46,349 likewise attenuated induction of locomotion by a further SSRI, fluvoxamine. CONCLUSIONS: The locomotor response to SSRIs of mice exposed to a novel environment is mediated via 5-HT1B and 5-HT2A receptors. In view of the importance of motor function to the etiology and treatment of depression, the significance of these observations to the clinical actions of SSRIs will be of interest to elucidate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12721776&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Conclusive evidence for distinct transporters for 5-hydroxytryptamine and noradrenaline in pulmonary endothelial cells of the rat.

Paczkowski NJ, Vuocolo HE, Bryan-Lluka LJ.

Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia.

The aims of this study were to obtain conclusive evidence about the roles of a 5-hydroxytryptamine [5-HT] transporter and uptake1 in the dissipation of 5-HT in the lungs of the rat and to compare the properties of the 5-HT transporter in rat lungs with that in other tissues, including brain and platelets. In the first part of the study, the IC50 values of a range of selective inhibitors and substrates of the 5-HT transporter or uptake1 were determined for inhibition of uptake of 5-HT or noradrenaline in intact perfused lungs of rats. Monoamine oxidase was inhibited and, in experiments with noradrenaline, catechol-O-methyltransferase was also inhibited. Initial rates of uptake of 5-HT or noradrenaline were measured in lungs perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min, in the absence or presence of at least three concentrations of paroxetine, citalopram, fluoxetine, 7-methyltryptamine, tryptamine, nisoxetine, imipramine, 5-HT, desipramine, (+)-oxaprotiline, cocaine or tyramine. The results showed that pharmacologically distinct transporters are involved in the uptake of 5-HT and noradrenaline in rat lungs, since there was no significant correlation between the IC50 values for inhibition of 5-HT and noradrenaline uptake in the lungs. However, there were significant correlations between the IC50 values for (a) inhibition of 5-HT uptake in rat lungs and of uptake by the 5-HT transporter in rat brain and (b) inhibition of noradrenaline uptake in rat lungs and of uptake1 in rat phaeochromocytoma PC-12 cells. The results support the conclusion that 5-HT uptake in rat lungs occurs, at least predominantly, by a 5-HT transporter which is very similar to or the same as that in other tissues, such as the brain, and provide further evidence for transport of noradrenaline by uptake1. Further experiments were carried out to determine whether there is any transport of 5-HT by uptake1 or of noradrenaline by the 5-HT transporter in rat lungs. Lungs were perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min in the absence or presence of 1 mumol/l citalopram, desipramine, or citalopram and desipramine. The results showed that there was no evidence of any transport of 5-HT in the lungs by uptake1 or of noradrenaline by the 5-HT transporter, in that desipramine had no effect on 5-HT uptake (in the absence or presence of citalopram) and citalopram had no effect on noradrenaline uptake (in the absence or presence of desipramine). The final series of experiments was carried out to determine whether, at high concentrations of the amine, there is any interaction of 5-HT with uptake1 or of noradrenaline with the 5-HT transporter. Noradrenaline, at a concentration of 10 mumol/l, did not affect 5-HT uptake in lungs perfused with 2 nmol/l 3H-5-HT for 2 min (uptake1 inhibited), but 50 mumol/l 5-HT inhibited noradrenaline uptake by 56% in lungs perfused with 2 nmol/l 3H-noradrenaline for 2 min (5-HT transporter inhibited). These and the above results show that the 5-HT transporter appears to be exclusively responsible for 5-HT uptake in rat lungs, despite the possible interaction of 5-HT at high concentrations with the uptake1 transporter in the cells. On the other hand, noradrenaline is transported exclusively by uptake1 in the lungs, and there is no evidence that it interacts with the 5-HT transporter, even at high concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8935709&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Determination of citalopram enantiomers in human plasma by liquid chromatographic separation on a Chiral-AGP column.

Haupt D.

Uppsala University, Biomedical Centre, Sweden.

A liquid chromatographic method for the quantitative analysis of S-(+)- and R-(-)-citalopram in human plasma has been developed and validated. The enantiomers of citalopram and the internal standard, R-(+)-propranolol, were extracted from alkaline plasma with 2% n-butanol in n-hexane. After a clean-up step, the organic phase was evaporated and the residues dissolved in 50-100 microliters of 0.001 M HCl. The separation was performed on a Chiral-AGP column with 3.0 mM N-dodecyl-N,N-dimethylammonio-3-propanesulfonate and 10 mM hexanoic acid in phosphate buffer pH 6.5 as the mobile phase. The limit of detection was estimated to be 1 ng/ml (S/N approximately equal to 3) for each enantiomer monitoring UV absorption at 240 nm. In the range studied, 2.31-191 ng/ml, the recoveries were quantitative and the coefficients of variations were between 2.47% and 11.5%.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8953171&dopt=Abstract citalopram escitalopram Lexapro