citalopram Celexa
Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram.

Neckelmann D, Bjorkum AA, Bjorvatn B, Ursin R.

Department of Physiology, University of Bergen, Norway.

The sleep and waking and EEG power spectrum effects of the putative 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.) were studied alone and in co-administration with the selective serotonin re-uptake inhibitor citalopram (5.0 mg/kg, i.p.) in the rat. Citalopram, as in a prior dose-response study, reduced REM sleep. In addition, a slight increase in NREM sleep was observed. Citalopram reduced NREM fronto-parietal (FP) EEG power density in the 5-20 Hz range. When administered alone, NAN-190 suppressed REM sleep in the first 2 h, and reduced SWS-2 in the first 4 after administration. NAN-190 also suppressed selectively NREM sleep slow-wave activity in both fronto-frontal (FF) and FP EEG power spectrum. When administered in combination with citalopram, an attenuation of the power density reduction in the 7-15 Hz range in the FF EEG of citalopram alone, was observed. However, the EEG power spectral density and REM sleep suppressive effects of NAN-190 were both augmented. The results are compatible with the notion that serotonin is involved in the modulation of the slow wave activity in the EEG during NREM sleep. The results are cordant with other data suggesting that postsynaptic 5-HT1A stimulation might increase slow wave activity in the NREM EEG, and that serotonergic stimulation of other receptor subtypes (possibly 5-HT2) may decrease slow wave activity in the NREM EEG.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8800653&dopt=Abstract citalopram Celexa



citalopram Celexa
(-)-Pindolol, but not buspirone, potentiates the citalopram-induced rise in extracellular 5-hydroxytryptamine.

Hjorth S.

Department of Pharmacology, University of Goteborg, Sweden. stephan.hjorth pharm.gu.se

Recent open clinical studies suggest that pindolol and buspirone may enhance the efficacy and/or shorten the latency to antidepressant action of selective serotonin reuptake inhibitors (SSRI) in unipolar major depressive disorder. The present investigation addressed the possibility that these agents share the ability to enhance the extracellular 5-hydroxytryptamine (5-HT)-elevating response to the SSRI citalopram. For the purpose, in vivo microdialysis in the rat ventral hippocampus was employed. (-)-Pindolol (8 mg/kg s.c.) augmented the citalopram (5 mg/kg s.c.)-induced rise of extracellular 5-HT levels, whereas buspirone (5 mg/kg s.c.) failed to do so. This effect of (-)-pindolol probably reflects its ability to block 5-HT1A autoreceptors, thereby abating the citalopram-induced indirect activation of these sites (secondary to the inhibition of 5-HT reuptake and elevation of extracellular 5-HT in the midbrain raphe). The lack of effect of buspirone in this model indicates that the clinically observed antidepressant augmentation action of buspirone is not mediated indirectly, via enhanced extracellular levels of 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8813565&dopt=Abstract citalopram Celexa



citalopram Celexa
Chronic citalopram and fluoxetine treatments upregulate 5-HT2c receptors in the rat choroid plexus.

Laakso A, Palvimaki EP, Kuoppamaki M, Syvalahti E, Hietala J.

Department of Pharmacology, University of Turku, Finland.

The effects of chronic (for 14 days) citalopram and fluoxetine treatments with three doses (2.5, 10, and 20 mg/kg) and withdrawal times (24 hours, 68 hours, and 14 days) on 5-HT2C (formerly 5-HT1C) receptors in the rat brain choroid plexus were studied with quantitative receptor autoradiography in two separate experiments. Chronic citalopram treatment caused a consistent and dose-related increase in the density of 5-HT2C receptors (up to 90%). This effect was slightly more pronounced when measured with an antagonist ligand ([3H]mesulergine) than with an agonist ligand [(+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane ([125I]DOI)]. The upregulation was most evident 24 hours after the last dose and disappeared thereafter rather rapidly. Chronic fluoxetine treatment also increased the density of 5-HT2C receptors 24 hours from the last dose, but the increase was accompanied by a reduced affinity and was less marked than that observed with citalopram. The changes in receptor characteristics were not observed consistently after the 68-hour withdrawal from fluoxetine. Furthermore, the upregulation of fluoxetine appeared not to be dose related or reflected by an increase in agonist binding. In conclusion, the results show that chronic citalopram and fluoxetine treatments induce an increase of choroid plexus 5-HT2C receptor density, but the effect is more marked with citalopram. These differences in the regulation of the 5-HT2C receptors may lead to pharmacodynamic differences between chronic citalopram and fluoxetine treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8840350&dopt=Abstract citalopram Celexa



citalopram Celexa
Effect of citalopram on the desensitization of serotonin-2A receptor-mediated calcium mobilization in rat glioma cells.

Kagaya A, Kugaya A, Hayashi T, Okamoto Y, Takebayashi M, Uchitomi Y, Yamawaki S.

Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, Minamiku, Hiroshima, Japan.

1. The authors have investigated the effect of citalopram, an effective antidepressant drug with selective serotonin (5-HT) uptake inhibition, on 5-HT-2A receptor-mediated intracellular calcium (Ca2+) rise in C6 cultured cells. 2. Citalopram, at concentrations of 10 and 30 mu M, did not significantly reduce the Ca2+ mobilization induced by 10 mu M 5-HT, indicating that citalopram has little affinity for 5-HT-2A receptors. 3. Citalopram did not alter a subsequent response to 5-HT after citalopram was pre-applied to the cells. 4. However, citalopram inhibited the desensitization of 5-HT-2A receptors. When the cells were pretreated with citalopram and 5-HT, the subsequent response to 5-HT was significantly greater than that obtained following pretreatment with 5-HT alone. 5. To investigate the mechanism of action of citalopram on the desensitization of 5-HT-2A receptors, NaF-induced cGMP generation was measured. Citalopram inhibited the generation of cGMP induced by NaF in C6 cells as well as W-7. 6. These results indicate that citalopram antagonized the desensitization of 5-HT-2A receptor-mediated Ca2+ mobilization and this antagonism may be mediated by a calmodulin-dependent pathway in C6 glioma cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8861185&dopt=Abstract citalopram Celexa



citalopram Celexa
Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor.

Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J.

Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic antidepressant (TCA) imipramine with the rat serotonin 5-HT2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT2C and 5-HT2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT2C receptor in the choroid plexus, with a Ki value for inhibition of [3H]mesulergine binding of 55.4 nM. The Ki values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT2C receptor without exhibiting inverse agonist activity. [3H]Ketanserin (5-HT2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT2A and 5-HT2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8876023&dopt=Abstract citalopram Celexa



citalopram Celexa
Serotonergic modulation of striatal D2 dopamine receptor binding in humans measured with positron emission tomography.

Tiihonen J, Kuoppamaki M, Nagren K, Bergman J, Eronen E, Syvalahti E, Hietala J.

Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, Finland.

The modulating effect of serotonergic drugs on the striatal dopamine neurotransmission has remained controversial, and there are no published data on serotonin-dopamine interaction obtained from living human brain. Citalopram is a selective serotonin reuptake inhibitor widely used in the treatment of depression (20-40 mg/day). We measured the effects of acute (20 mg, per os) and chronic (20 mg/day for 14 days) doses of citalopram and placebo intake on [11C]-raclopride binding to striatal D2-receptors in eight healthy volunteers by using positron emission tomography. Although the effect magnitude was not large, the results indicate that chronic citalopram intake slightly decreases the raclopride binding which may reflect increased dopamine release in the striatum. In addition, after 14 days there was a high correlation between the citalopam plasma levels and the decrease in the [11C]-raclopride binding in both the caudate and the putamen, although statistically significant effect in the raclopride binding potential was more pronounced in the putamen. This report suggests functional interaction of brain dopaminergic and serotonergic systems in vivo in man.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8878342&dopt=Abstract citalopram Celexa



citalopram Celexa
Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells.

Xia Z, DePierre JW, Nassberger L.

Wallenberg Laboratory, Department of Biochemistry, University of Stockholm, Sweden.

Tricyclic antidepressants (TCAs) are widely used in treating depressive disorders. It has been demonstrated that, for instance, IL-1 beta and IL-6 inhibit the HPA axis, which plays a role in the development of depressions. Therefore. we were interested in investigating how TCAs influence cytokine release by T lymphocytes and monocytes respectively. Cells were incubated with either 5 microM clomipramine, 15 microM imipramine or 20 microM citalopram. IL-2 release was suppressed to 60% of the control values by clomipramine and imipramine (p = 0.001; p = 0.000), but citalopram was found to cause a much weaker inhibition (only 18%) (p = 0.16). INF-gamma release was affected to a lower degree than IL-2 release, and imipramine (34%) (p = 0.054) was more potent than clomipramine (24%) (p = 0.16) and citalopram (12%) (p = 0.059) in this case. Monocytes incubated with TCA for 4 h exhibited only limited inhibition of IL-1 beta and IL-6 release, i.e., 6-25% for all three compounds. The corresponding value for TNF-alpha release was 20-45% inhibition, with citalopram being the weakest inhibitor. After 10 h of monocytes to LPS exposure, all three compounds exerted a strong inhibition of IL-1 beta and TNF-alpha release, i.e., 60-70% with p-values below 0.012 for all of them. However the inhibition of IL-6 release was less than 35%. Citalopram was equality as potent as imipramine and clomipramine in inhibiting IL-6 release after long-term exposure of monocytes to LPS. All three TCAs elevated intracellular cAMP concentrations significantly in T lymphocytes and monocytes (p < 0.001).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8880223&dopt=Abstract citalopram Celexa



citalopram Celexa
Citalopram: differential sleep/wake and EEG power spectrum effects after single dose and chronic administration.

Neckelmann D, Bjorvatn B, Bjorkum AA, Ursin R.

Department of Physiology, University of Bergen, Norway. dag.neckelmann phs.ulaval.ca

The sleep/wake effects of the selective serotonin re-uptake inhibitor citalopram were studied in both a single-dose study with three dose levels (0.5, 2.0 and 5.0 mg/kg), and a 5-week chronic administration study (15 mg/kg/24 h). Single doses of citalopram resulted in a dose-dependent inhibition of rapid eye movement (REM) sleep. After chronic citalopram treatment there was a sustained REM sleep inhibition. Single doses of citalopram resulted in only minor changes in non-REM (NREM) sleep as well as in NREM EEG power spectral density. Chronic administration resulted in a major shift from SWS-2 to SWS-1. The observed corresponding changes in EEG power density were regional. A 30 to 40 percent reduction of power density in the 0.5-15 Hz range in the fronto-parietal EEG derivation was seen for the whole 8-h registration period. In the fronto-frontal EEG derivation only minor changes were seen. A decreasing trend in NREM sleep power density between 0.5 and 7 Hz, usually seen during the course of the light period, was not observed in the chronic condition, but was seen in control and single-dose condition, suggesting altered diurnal distribution of slow wave activity in the chronic condition. The data indicate that acute and chronic administration of citalopram shows clear differences in sleep effect, which may be caused by alteration of serotonergic transmission, and may be related to the antidepressant effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8883829&dopt=Abstract citalopram Celexa