citalopram Celexa
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 Celexa



citalopram Celexa
Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain.

Romero L, Bel N, Artigas F, de Montigny C, Blier P.

Department of Neurochemistry, CID, Consejo Superior de Investigaciones Cientificas (CSIC), Barcelona, Spain.

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8887989&dopt=Abstract citalopram Celexa



citalopram Celexa
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 Celexa



citalopram Celexa
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 Celexa



citalopram Celexa
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 Celexa



citalopram Celexa
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%.

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citalopram Celexa
Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo.

Hjorth S, Bengtsson HJ, Milano S.

Department of Pharmacology, University of Goteborg, Sweden. Stephan.Hjorth pharm.gu.se

In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (-)-penbutolol in this regard. The selective 5-HT1A receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed 5-HT1A/1B/beta-adrenoceptor antagonist (-)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local "reverse' dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (-)-penbutolol-induced augmentation proved stereoselective and not mediated by beta-adrenoceptors (no effect of s.c. (+)-penbutolol, or beta 1- and beta 2-adrenoceptor blockers (betaxolol, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT1A receptors nor beta-adrenoceptors appear to be involved.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8982649&dopt=Abstract citalopram Celexa



citalopram Celexa
Increased noradrenaline efflux induced by local infusion of fluoxetine in the rat frontal cortex.

Hughes ZA, Stanford SC.

Department of Pharmacology, University College London, UK.

In microdialysis experiments in vivo, local infusion of either the selective serotonin reuptake inhibitor, fluoxetine, or the selective noradrenaline uptake inhibitor, desipramine, increased noradrenaline efflux in rat frontal cortex. Synaptosomal uptake of [3H]noradrenaline was used to test whether inhibition of uptake could contribute to this effect of fluoxetine. Low concentrations of fluoxetine were less effective than desipramine at inhibiting [3H]noradrenaline uptake; both compounds were more potent than the selective serotonin reuptake inhibitor, citalopram. To investigate whether this inhibition of uptake involved an action on noradrenergic neurones, experiments compared the effects of a noradrenergic lesion, induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the inhibition of uptake by fluoxetine, desipramine and citalopram. The lesion reduced [3H]noradrenaline uptake in the presence of fluoxetine and citalopram but increased it in the presence of desipramine. The results suggest both that inhibition of noradrenaline uptake could contribute to the actions of fluoxetine and that a non-noradrenergic mechanisms is a target for this action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8982723&dopt=Abstract citalopram Celexa