citalopram escitalopram Lexapro
Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram.

Husum H, Mikkelsen JD, Hogg S, Mathe AA, Mork A.

Department of Neurobiology, H. Lundbeck A/S, Ottiliavej 9, DK-2500, Copenhagen-Valby, Denmark.

Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvulsive stimuli (ECS) has been shown to increase mRNA and peptide levels of NPY in rat brain tissue. Consequently, parameters reflective of NPYergic neurotransmission were studied in the hippocampus of rats following chronic treatment with lithium, ECS or the selective serotonin re-uptake inhibitor (SSRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) treatments caused a marked increase in levels of preproNPY mRNA in the CA1 area and dentate gyrus (DG). This increase was accompanied by an increase in extracellular levels of NPY in the dorsal hippocampus of freely moving rats as determined by microdialysis, suggesting that lithium and ECS treatments lead to an increased biosynthesis and release of NPY in this area. (125)I-peptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG following the same treatments, showing that the increased release is accompanied by a down-regulation of corresponding binding sites. In contrast, citalopram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in (125)I-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extracellular NPY in the hippocampus were unaffected. The results indicate that various agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram all increase NPYergic neurotransmission in the hippocampus by distinct modes of action. Moreover, NPY (6 microg) given intracerebroventricularly (i.c.v.) induced an antidepressant-like effect in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of various antidepressant treatments in the alleviation of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10818262&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Changes in [3H]citalopram binding in cerebral cortex after antidepressant treatment in monoamine-impaired rats.

Pruus K, Rudissaar R, Skrebuhhova T, Allikmets L, Matto V.

Department of Pharmacology, University of Tartu, Estonia.

The [3H]citalopram binding after three weeks vehicle, desipramine 10 mg/kg or citalopram 5 mg/kg treatment was studied in the cerebral cortex of normal, DSP-4-, and p-CPA-impaired rats. The DSP-4 50 mg/kg treatment decreased the affinity (Kd), but increased the maximal number of the apparent binding sites (Bmax) of the 5-hydroxytryptamine transporter (5-HTT). This effect was reversed by desipramine 10 mg/kg treatment. The p-CPA 350 mg/kg treatment decreased the Bmax value while the antidepressant treatment did not influence this parameter. In conclusion, our experiments demonstrate that the monoaminergic impairment induced by DSP-4 and p-CPA treatment evokes opposite changes in the 5-HTT binding characteristics and these changes are partially reversed by the chronic antidepressant treatment.

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citalopram escitalopram Lexapro
Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment.

Olausson P, Engel JA, Soderpalm B.

Department of Pharmacology, Institute of Physiology and Pharmacology, Goteborg University, Box 431, SE-405 30, Goteborg, Sweden. peter.olausson pharm.gu.se

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.

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citalopram escitalopram Lexapro
Augmentation with a 5-HT(1A), but not a 5-HT(1B) receptor antagonist critically depends on the dose of citalopram.

Cremers TI, de Boer P, Liao Y, Bosker FJ, den Boer JA, Westerink BH, Wikstrom HV.

Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands. t.i.f.h.cremers farm.rug.nl

Pharmacokinetic and pharmacodynamic parameters of the selective serotonin reuptake inhibitor 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril (citalopram) were determined in order to find optimal conditions for augmentation of its effect on extracellular serotonin [5-hydroxytryptamine (5-HT)] through blockade of 5-HT(1A) and 5-HT(1B) autoreceptors. Citalopram dose-dependently (0.3-10 micromol/kg s.c.) increased serotonin levels in ventral hippocampus of conscious rats. At plasma levels above approximately 0.15 microM, the effect of citalopram on extracellular 5-HT was augmented by both a 5-HT(1A) [N-[2-[4-(2-mehoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridil) cyclohexa necarboxamide trihydrochloride (Way 100635), 1 micromol/kg s.c.] and a 5-HT(1B) receptor antagonist (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy]-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935), 1 micromol/kg s.c.). However, at plasma levels of the selective serotonin reuptake inhibitor below 0.15 microM, the effects of the antagonists diverged viz. the 5-HT(1B) receptor antagonist was still able to potentiate citalopram's effect on extracellular 5-HT, while the 5-HT(1A) receptor antagonist was no longer effective. These results suggest that in contrast to 5-HT(1B) autoreceptors, indirect activation of 5-HT(1A) autoreceptors by citalopram is critically related to the dose of selective serotonin reuptake inhibitor administered. The latter may have consequences for selective serotonin reuptake inhibitor augmentation strategies with 5-HT(1A) receptor antagonists in the therapy of depression and anxiety disorders.

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citalopram escitalopram Lexapro
Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram.

Cremers TI, Spoelstra EN, de Boer P, Bosker FJ, Mork A, den Boer JA, Westerink BH, Wikstrom HV.

Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands. t.i.f.h.cremers farm.rug.nl

Rats were chronically treated with the selective serotonin re-uptake inhibitor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril ], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0.3 mcM citalopram were maintained for 15 days. Citalopram plasma levels dropped below pharmacologically active concentrations 48 h after removal of the minipumps. Although chronic treatment with citalopram did induce an attenuated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment was observed when 5-HT(1B) receptor function was evaluated with a local infusion of 5-HT(1B/D) receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of citalopram. It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT(1A) receptors, the absence of augmented effects of citalopram on 5-HT levels indicates that other mechanisms compensate for the loss of autoreceptor control.

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citalopram escitalopram Lexapro
Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum.

Kameda K, Kusumi I, Suzuki K, Miura J, Sasaki Y, Koyama T.

Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan. kenkamed med.hokudai.ac.jp

Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum were studied. Repeated administration of citalopram increased the amount of dopamine D2 receptors, the level of dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene. Single administration of citalopram also increased the level of dopamine D2 receptor mRNA with a maximum effect in 2-4 h after the treatment, and the transcription rate of the dopamine D2 receptor gene. The administration of 5-hydroxytryptophan (5-HTP) also increased the level of dopamine D2 receptor mRNA. These results suggest that the increase in the dopamine D2 receptor expression induced by citalopram may be owing, at least partially, to the stimulation of the dopamine D2 receptor gene transcription, and that serotonin (5-HT) may mediate the effects of citalopram in the induction of dopamine D2 receptor expression.

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citalopram escitalopram Lexapro
The effect of acute citalopram on extracellular 5-HT levels is not augmented by lithium: an in vivo microdialysis study.

Wegener G, Linnet K, Rosenberg R, Mork A.

Institute for Basic Psychiatric Research, Department of Biological Psychiatry, DK-8240, Risskov, Denmark. wegener dadlnet.dk

A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentative strategy. Since lithium has been demonstrated to affect 5-HT neurotransmission, we examined the effect of acute and subchronic lithium on 5-HT levels after a challenge with citalopram. We found that subchronic administration of lithium increases extracellular 5-HT baseline level and decreases the extracellular 5-HIAA baseline. However, we found no evidence that the effect of acute citalopram on extracellular 5-HT levels is augmented by acute or subchronic lithium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10899300&dopt=Abstract citalopram escitalopram Lexapro