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Effect of serotonin reuptake inhibitor on syndrome development in obese hyperglycemic mice (Umea ob/ob).

Thrybom T, Rooth P, Lindstrom P.

Department of Integrative Medical Biology, Umea University, Sweden.

These experiments tested the effect of 10 to 30 mg, citalopram/kg body weight on food intake, weight increase, and blood glucose levels in young obese hyperglycemic mice (Umea ob/ob). A leptin defect in ob/ob mice results in hyperphagia, hyperglycemia, and increased body weight compared with normal mice. Citalopram had no effect on weight increase in ob/ob mice aged 3 to 10 weeks, when the weight increase is most rapid. Citalopram reduced the weight increase at the age 10 to 19 weeks. Food intake reaches a maximum at age 7 to 10 weeks and then decreases. The reduction was more rapid in citalopram-treated mice. The weight of feces paralleled the food intake. Citalopram treatment had no effect on serum insulin levels in 15-week-old mice. Blood sugar values in fed mice reached a peak at age 7 weeks (21.7 +/- 1.7 mmol/L in controls and 22.3 +/- 1 mmol/L in citalopram-treated mice). After that, blood sugar values decreased. The decrease was more pronounced in citalopram-treated mice (P < .01 compared with controls). Blood glucose levels were lower at ages 12 to 15 weeks in female ob/ob control mice (13.6 +/- 2.5 mmol/L v 19.0 +/- 0.6 mmol/L in male control mice; P < .05). The effect of citalopram was the same in male and female mice. There was a close correlation between accumulated food intake and blood glucose values in individual animals. At age 3 to 10 weeks, ob/ob mice have a high beta-cell proliferation rate, and they have large islets of Langerhans. This was not affected by citalopram treatment. Our findings show that the serotonergic system plays a role as a regulator of food intake over shorter periods, and this is also true in the absence of leptin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11229420&dopt=Abstract citalopram escitalopram Lexapro



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Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala.

Bosker FJ, Cremers TI, Jongsma ME, Westerink BH, Wikstrom HV, den Boer JA.

Department of Psychiatry, Academic Hospital Groningen, the Netherlands. f.bosker acggn.azg.nl

Microdialysis was used to assess the involvement of postsynaptic 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in the regulation of extracellular 5-HT in the amygdala. Local infusion of the 5-HT(1A) receptor agonist flesinoxan (0.3, 1, 3 microM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level. Systemic administration of citalopram (10 micromol/kg) increased 5-HT to 175% of basal level. Local infusion of 1 microM of the 5-HT(1A) receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5-HT level. 5-HT(1A) receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 microM flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration-time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 micromol/kg), which increased 5-HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 microM WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5-HT(1A) receptor-mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11259482&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.

Dekeyne A, Iob L, Millan MJ.

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France. anne.dekeyne fr.netgrs.com

RATIONALE: The discriminative stimulus (DS) properties of the selective serotonin (5-HT) uptake inhibitor (SSRI), citalopram, are mediated by 5-HT2C receptors. Interestingly, the "atypical" antidepressants, mianserin and mirtazapine, behave as antagonists at 5-HT2C receptors. OBJECTIVE: Herein, we evaluated the influence of mianserin and mirtazapine upon the DS effects of citalopram. METHODS: In a two-lever drug discrimination procedure, rats initially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline were retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequently, generalization and antagonist studies were conducted with mianserin and mirtazapine. RESULTS: Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response rates. Their effective dose50s were 0.1 and 1.4 mg/kg, s.c., respectively. CONCLUSION: These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11271412&dopt=Abstract citalopram escitalopram Lexapro



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Differential effects of fluoxetine and citalopram treatments on serotonin 5-HT(2C) receptor occupancy in rat brain.

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

Department of Pharmacology and Clinical Pharmacology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.

Ex vivo receptor occupancy measurements were performed in order to study the effects of the serotonin reuptake inhibitors fluoxetine and citalopram on serotonin 5-HT(2C) receptors. To determine the degree of 5-HT(2C) receptor occupancy, [(3)H]mesulergine binding in brain sections containing rat choroid plexus was measured at various time-points after drug injection. For comparison, [(3)H]ketanserin binding to frontal cortex 5-HT(2A) receptors was measured. Fluoxetine treatments (10 and 20 mg/kg) resulted in 5-HT(2C) receptor occupancy of up to 25 and 43%, respectively. Fluoxetine (20 mg/kg) caused a persistent effect: at the 24 h time-point, 23% of 5-HT(2C) receptors were still occupied. Citalopram treatment did not result in marked 5-HT(2C) receptor occupancy. Neither drug caused significant 5-HT(2A) receptor occupancy. In conclusion, the results demonstrate pharmacodynamic differences between fluoxetine and citalopram at the level of 5-HT(2C) receptors. These findings provide evidence that direct occupancy of 5-HT(2C) receptors may contribute to the mechanism of action of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11281975&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Costs and outcomes of use of amitriptyline, citalopram and fluoxetine in major depression: exploratory study.

Hosak L, Tuma I, Hanus H, Straka L.

Department of Psychiatry, Charles University in Prague, Faculty of Medicine in Hradec Kralove. hosak lfhk.cuni.cz

BACKGROUND: The increasing cost of pharmaceuticals in the Czech Republic has led to the restriction on prescriptions of expensive new antidepressants. The aim of the study was to compare the costs and outcomes of using amitriptyline, citalopram and fluoxetine in the treatment of major depression. METHODS: Ninety patients (69 women) with a mean age of 44.5 years (S.D. = 14.3) suffering from major depression were treated with amitriptyline (N = 31), citalopram (N = 29) and fluoxetine (N = 30). Direct medical costs and effectiveness (indicated by the number of hospitalization-free days) were assessed in a prospective, open, intent-to-treat study. RESULTS: Neither cost nor effectiveness were significantly different among the treatment groups. CONCLUSION: Amitriptyline treatment is not less expensive nor more effective than citalopram or fluoxetine therapies. There is no advantage in restricting patients from treatment with SSRIs, which have fewer adverse effects and a decreased risk of a lethal overdosage in comparison with tricyclic antidepressants.

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Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex.

Golembiowska K, Dziubina A.

Department of Pharmacology, Institute of Pharacology, Polish Academy of Sciences, Krakow. nfgolemb cyf-kr.edu.pl

The present study was designed to determine whether peripheral administration of the selective serotonin reuptake inhibitor (SSRI) citalopram influenced glutamate and aspartate release in the rat prefrontal cortex using in vivo microdialysis. Citalopram was given acutely at doses of 10 and 20 mg/kg or chronically at a dose of 10 mg/kg daily for two weeks, in both cases by intraperitoneal (ip) route. Citalopram given at a single dose of 20 mg/kg, but not 10 mg/kg, significantly inhibited release of glutamate and aspartate induced by sodium channel activator, veratridine (100 microM). Glutamate and aspartate release was also diminished in animals treated chronically with citalopram. Citalopram did not affect extracellular level of 5-hydroxytryptamine (5-HT) after acute doses, but increased it after chronic administration. On the other hand, single and repeated doses of the drug inhibited veratridine-evoked 5-HT release. Neither single nor chronic treatment with citalopram influenced spontaneous and evoked dopamine (DA) release. The results suggest that in the presence of depolarizing agent, e.g. under conditions resembling a disturbed homeostasis of neuronal network, antidepressant drugs with profile of SSRI may influence excitatory systems in the brain. This effect does not seem to be dependent on the interaction with 5-HT or DA neurotransmission, but rather some inhibitory modulators stimulated in stress situations may contribute to the observed results.

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Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors.

Szabo ST, de Montigny C, Blier P.

Sustained administration of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) citalopram for 2, 14, and 21 d, and paroxetine for 2 and 21 d (20 and 10 mg/kg.d, respectively, s.c. using osmotic minipumps) produced a gradual decrease in spontaneous firing activity of locus coeruleus (LC) noradrenergic neurons. In contrast, sustained desipramine administration for 2 and 21 d (10 mg/kg.d) robustly reduced LC firing activity, though only to the same extent, following these two treatment periods. The enhancement of the firing rate of LC neurons produced by the 5-HT1A agonist 8-OH-DPAT (10-50 &mgr;g/kg, i.v.) in desipramine- and citalopram-treated rats was abolished, indicating a desensitization of 5-HT1A receptors. However, the attenuation of the firing rate of LC neurons induced by the 5-HT2 agonist DOI (5-50 &mgr;g/kg, i.v.) was decreased approx. 2-fold in citalopram-treated rats but not significantly altered in desipramine-treated rats. Since 5-HT neurons exert a tonic inhibitory effect on LC neurons, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. In conclusion, SSRIs attenuate the activity of noradrenergic neurons with a delay that is consistent with their beneficial effect in depression and some anxiety disorders, such as panic, generalized and social anxiety disorders. However, given the hyperadrenergic state often observed in anxiogenic conditions the latter phenomenon is believed to contribute more to the anxiolytic effect of SSRIs than to their antidepressant action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11343573&dopt=Abstract citalopram escitalopram Lexapro