citalopram escitalopram Lexapro
Effect of 5-HT1A receptor antagonists on citalopram-induced increase in extracellular serotonin in the frontal cortex, striatum and dorsal hippocampus.

Invernizzi R, Velasco C, Bramante M, Longo A, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

The aim of the present study was to compare the effects of citalopram, either alone or combined with 5-HT1A receptor antagonists, on extracellular serotonin levels in brain regions innervated by the dorsal or median raphe nuclei. Using intracerebral microdialysis in awake rats with separate probes in the frontal cortex or dorsal hippocampus, we studied the ability of 8 mg/kg s.c. (-)penbutolol, a beta-adrenoceptor antagonist with antagonist action at 5-HT1A and 5-HT1B receptors, and 0.3 mg/kg s.c. WAY-100635, a selective 5-HT1A receptor blocker, to modify the effect of 1 and 10 mg/kg i.p. citalopram on extracellular serotonin. Both doses of citalopram had more effect on extracellular serotonin levels in the dorsal hippocampus than in the frontal cortex. The effect of 1 mg/kg citalopram was significantly potentiated by (-)penbutolol in the frontal cortex only, but a clear-cut potentiation of the effect of citalopram was seen in both regions at a dose of 10 mg/kg. The effect of 10 mg/kg citalopram was potentiated by WAY-100635 in the frontal cortex but not in the dorsal hippocampus. In a second set of experiments, the combined effect of WAY-100635 and citalopram was studied in the same rat implanted with vertical probes in the striatum and dorsal hippocampus. Citalopram (1 and 10 mg/kg i.p.) raised extracellular serotonin to a similar extent in both regions. However, 0.3 mg/kg s.c. WAY-100635 potentiated the effect of 10 mg/kg citalopram in the striatum but not in the dorsal hippocampus. The results suggest that only a combined blockade of 5-HT1A and 5-HT1B receptors potentiates the effect of citalopram on extracellular concentrations of serotonin in the dorsal hippocampus. The findings may be relevant in designing clinical trials aimed at enhancing the antidepressant action of selective serotonin re-uptake inhibitors by combining them with serotonin receptor antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9225271&dopt=Abstract citalopram escitalopram Lexapro



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Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5-HT: this effect persists after repeated citalopram treatment.

Gundlah C, Hjorth S, Auerbach SB.

Department of Biological Sciences, Rutgers University, Nelson Laboratories, Piscataway, New Jersey, USA.

The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (-)+penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug.

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Chronic citalopram treatment induces time-dependent changes in the expression and DNA-binding activity of transcription factor AP-2 in rat brain.

Berggard C, Damberg M, Oreland L.

Department of Neuroscience, Unit of Pharmacology, Uppsala University, PO Box 593 BMC, SE-751 24, Uppsala, Sweden.

Imbalances in the midbrain monoaminergic systems have been implicated to play a role in neuropsychiatric conditions. Several genes in these systems have binding sites for transcription factor activating protein-2 (AP-2) in their regulatory regions. Thus, AP-2 may be a factor controlling the expression of genes in the monoaminergic systems important for maintaining normal psychiatric functions. The present study indicates that subchronic treatment with the antidepressant citalopram induces time-dependent changes in DNA-binding activity and levels of transcription factor AP-2 in rat whole brain. Rats were treated with citalopram (10 mg/kg) for 1, 3, 7 and 21 days. Animals treated for 7 days had significantly decreased DNA-binding activity and levels of AP-2 alpha and AP-2 beta isoforms when compared to saline-treated animals. There was no observed difference between citalopram- and saline-treated animals after 21 days. Elucidation of the molecular mechanisms underlying mental disorders is important for future drug development, where transcription factors might be important drug targets.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12480117&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Carrier-mediated serotonin release induced by d-fenfluramine: studies with human neuroblastoma cells transfected with a rat serotonin transporter.

Cinquanta M, Ratovitski T, Crespi D, Gobbi M, Mennini T, Simantov R.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The NMB human neuronal cell line, transfected with a newly prepared plasmid expressing rat serotonin transporter (NMB-rSERT), shows specific [3H]5-HT uptake which is blocked by citalopram and fenfluramine (F) stereoisomers with IC50 values (1 nM. 0.5 microM (dF) and and 5 microM (IF), respectively) which are similar to those found in rat brain synaptosomes. d-Fenfluramine (0.5 and 10 microM) also stimulates tritium release from NMB-rSERT cells preloaded with [3H-]-5-HT. The d-fenfluramine-induced [3H-]5-HT release is blocked by 0.3 microM citalopram and is dependent on the density of SERT expressed per cell, but is not affected by removal of Ca++ ions from the incubation medium. Manipulation of the Na+ gradient across the plasma membrane (replacing 60 mM NaCl with an equimolar concentration of KCl or choline) also induced [3H-]5-HT release from NMB-rSERT cells, which was inhibited by 0.3 microM citalopram. These results, together with the finding that NMB-rSERT cells preloaded with 500 nM unlabelled 5-HT take up [3H-]d-fenfluramine, make NMB-rSERT cells a valuable tool for studying the transporter-mediated exchange release induced by amphetamine derivatives.

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Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats.

Gobbi M, Crespi D, Foddi MC, Fracasso C, Mancini L, Parotti L, Mennini T.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties, citalopram (10 mg/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg/kg, p.o. twice a day for 21 days, 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of brain 5-HT uptake (sites) were found by measuring functional [3H]5-HT uptake and [3H]citalopram binding in cortical and hippocampal synaptosomes, and by [3H]citalopram binding autoradiography in the raphe nuclei (5-HT cell bodies) and the ventral tegmental area (5-HT axonal pathway). Chronic treatments had no effect on presynaptic 5-HT1B autoreceptors, functionally evaluated by measuring 5-HT1B-mediated inhibition of depolarization-induced [3H]5-HT release from cortical and hippocampal synaptosomes. Chronic citalopram or fluoxetine did not significantly affect the binding of [3H]BRL-43694 to 5-HT3 receptors in the rat brain cortex. Citalopram had no effect on [125I]SB-207710 binding to 5-HT4 receptors, measured by autoradiography in the substantia nigra. Negative results, such as those reported in the present study, could be due to a number of variables including the animal species, the treatment schedule or the brain areas considered, thus explaining the differences from some previous reports of significant effects of SSRI. However, our negative data are in agreement with many other published studies, suggesting that adaptive modifications of brain 5-HT transporters, terminal 5-HT1B receptors, 5-HT3 and 5-HT4 receptors may not be a general effect induced by all SSRI.

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citalopram escitalopram Lexapro
Efflux studies allow further characterisation of the noradrenaline and 5-hydroxytryptamine transporters in rat lungs.

James KM, Bryan-Lluka LJ.

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

The aim of the present study was to further characterise the noradrenaline and 5-hydroxytryptamine [5-HT] transporters in rat lungs by examining the efflux of noradrenaline and 5-HT, respectively. Lungs from rats were isolated and perfused via the pulmonary artery. After loading the tissue with 3H-5-HT or 3H-noradrenaline the efflux of the relevant amine from the lungs was examined for 15-25 min. The rate constant for efflux of 3H-5-HT increased by 81% when Na+ ions were removed from the perfusion solution; increased gradually when a selective 5-HT transporter inhibitor, 200 nM citalopram, was added to the perfusion solution for the final 6 min of efflux; and increased markedly and rapidly when substrates of the 5-HT transporter, tryptamine (18 microM) and 7-methyltryptamine (12 microM), were added for the final 6 min of efflux. These effects of the substrates were abolished by 1 microM citalopram, but were not significantly affected by 1 microM desipramine, a selective uptake, inhibitor. On the other hand, the previously described substrate-induced increase in the rate of efflux of noradrenaline was significantly reduced by desipramine but was unaffected by citalopram. The results show that efflux of 5-HT is mediated only by the 5-HT transporter, with no significant contribution of uptake1, and efflux of noradrenaline from rat lungs is mediated only by uptake1 and not by the 5-HT transporter. The effects of dopamine on the efflux of noradrenaline over a concentration range of 100-600 nM were investigated and the results showed that 50% of the maximal increase in the rate of efflux occurred at a concentration of 275 nM. This value did not differ from the Km for uptake of dopamine. This result implies that the only factor affecting the substrate-induced increase in noradrenaline efflux is the affinity of the substrate for uptake1. The efflux of noradrenaline was also examined in the absence and presence of two concentrations of desipramine (0.35 and 1.5 microM). Analysis of these results showed that uptake1 contributed approximately 81% and diffusion 19% to the total efflux of noradrenaline and that 90% of the total noradrenaline efflux was subject to reuptake by uptake1 into the pulmonary endothelial cells.

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Radiosynthesis and PET imaging of [N-methyl-11C]LY257327 as a tracer for 5-HT transporters.

Zea-Ponce Y, Baldwin RM, Stratton MD, al-Tikriti M, Soufer R, Schaus JM, Innis RB.

Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.

No-carrier-added [N-methyl-11C]LY257327 was synthesized by methylation of the free base of the desmethyl precursor LY214281 with [11C]methyl iodide in anhydrous acetonitrile. Synthesis time was 52 +/- 3 min, radiochemical yield (based on [11C]methyl iodide) was 35 +/- 8%, radiochemical purity was 99 +/- 1%, and specific activity at EOB was 3900 +/- 1300 mCi/mumol. Two in vivo studies in baboon were carried out before and after pretreatment with the selective serotonin reuptake inhibitor citalopram. The first experiment showed high accumulation of radioactivity in midbrain, striatum, and thalamus, with slightly lower accumulation in the occipital and cerebellum regions. The radioactivity concentration peaked 5 min postinjection, decreasing steadily for the rest of the scanning time. The second experiment (blocked with citalopram) showed only partial inhibition of incorporation in all of the same brain regions. Although [N-methyl-11C]LY257327 displayed high brain uptake (5% of injected dose at 5 min postinjection) and localized in serotonergic areas of the brain, its target-to-nontarget ratio and its insensitivity to citalopram blocking suggest that its accumulation is dominated by nonspecific uptake. Therefore, [N-methyl-11C]LY257327 is not a useful agent for measuring serotonin reuptake sites in vivo by positron emission tomography.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9228659&dopt=Abstract citalopram escitalopram Lexapro