citalopram Celexa
Effects of serotonin and noradrenaline uptake blockers on wakefulness and sleep in cats.

Hilakivi I, Kovala T, Leppavuori A, Shvaloff A.

The aim of the study was to examine the role of serotonergic (5-HT) and noradrenergic mechanisms in the regulation of wakefulness and sleep. For this purpose, adult cats with implanted electrodes for EEG, EOG and EMG were exposed to the 5-HT uptake blocker citalopram (0.1, 0.5 and 5.0 mg/kg intraperitoneally) and the noradrenaline uptake blocker prindamine (5 mg/kg intraperitoneally) at the start of continuous 16-hour sleep-wake recordings. Citalopram increased deep slow wave sleep and decreased REMS. Also prindamine decreased REMS but initially increased the proportion of time spent in the state of active wakefulness. Furthermore, to examine the interactions between 5-HT-nergic and noradrenergic mechanisms in the regulation of sleep, the administration of citalopram was preceded by intraperitoneal injections of phentolamine (10 mg/kg), an alpha-antagonist, and propranolol (5 mg/kg), a beta-antagonist. Phentolamine was totally ineffective against citalopram whereas propranolol partially counteracted the effects of citalopram on sleep. Prindamine was combined with the alpha-antagonists yohimbine (1 mg/kg), phentolamine (10 mg/kg) and prazosin (1 mg/kg) or with the beta-antagonist propranolol (5 mg/kg). Yohimbine was without any effect on REMS, phentolamine partly antagonized prindamine-induced decrease in the percentage of REMS, and prazosin only prolonged REMS latency and reduced deep SWS as well. Propranolol partially antagonized the prindamine-induced initial increase in active wakefulness time.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine.

D'Amato RJ, Largent BL, Snowman AM, Snyder SH.

Citalopram is a potent and selective inhibitor of neuronal serotonin uptake. In rat brain membranes [3H]citalopram demonstrates saturable and reversible binding with a KD of 0.8 nM and a maximal number of binding sites (Bmax) of 570 fmol/mg of protein. The drug specificity for [3H]citalopram binding and synaptosomal serotonin uptake are closely correlated. Inhibition of [3H]citalopram binding by both serotonin and imipramine is consistent with a competitive interaction in both equilibrium and kinetic analyses. The autoradiographic pattern of [3H]citalopram binding sites closely resembles the distribution of serotonin. By contrast, detailed equilibrium-saturation analysis of [3H]imipramine binding reveals two binding components, i.e., high affinity (KD = 9 nM, Bmax = 420 fmol/mg of protein) and low affinity (KD = 553 nM, Bmax = 8560 fmol/mg of protein) sites. Specific [3H]imipramine binding, defined as the binding inhibited by 100 microM desipramine, is displaced only partially by serotonin. Various studies reveal that the serotonin-sensitive portion of binding corresponds to the high affinity sites of [3H]imipramine binding whereas the serotonin-insensitive binding corresponds to the low affinity sites. Lesioning of serotonin neurons with p-chloroamphetamine causes a large decrease in [3H]citalopram and serotonin-sensitive [3H]imipramine binding with only a small effect on serotonin-insensitive [3H]imipramine binding. The dissociation rate of [3H]imipramine or [3H]citalopram is not altered by citalopram, imipramine or serotonin up to concentrations of 10 microM. The regional distribution of serotonin sensitive [3H]imipramine high affinity binding sites closely resembles that of [3H]citalopram binding.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
Effect of citalopram, amineptine, imipramine and nortriptyline on stress-induced (footshock) analgesia in rats.

Testa R, Angelico P, Abbiati GA.

The influence of the oral administration of different doses of citalopram (5, 15 and 45 mg/kg), imipramine (15, 30, 45 and 60 mg/kg), nortriptyline (15, 45 and 60 mg/kg) and amineptine (45 mg/kg) on stress-induced analgesia has been studied in anaesthetized rats. None of the administered antidepressants seem to have appreciable analgesic activity when analgesia is tested by the tail-immersion method. Citalopram, imipramine and nortriptyline, but not amineptine, increase the analgesia induced by inescapable footshock delivered continuously for 2 min to rats. Citalopram is the most potent drug. Our results support the suggested importance of 5-HT and noradrenaline terminals, but not those of dopamine, in the mediation of the stress-induced analgesia and seem to support the hypothesis that the analgesic activity of antidepressants is partially related to their modulating effects on the endogenously released opioid peptides involved in the endogenous pain inhibitory systems.

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citalopram Celexa
Serotonin uptake inhibitors and the prejunctional effects of serotonin on peripheral sympathetic nerves.

Adler-Graschinsky E, Butta NV, Elgoyhen AB.

The experiments were designed to study whether the inhibitors of the uptake of serotonin (5-HT) potentiated the prejunctional effects of 5-HT on peripheral sympathetic nerves. The effect of two selective 5-HT uptake inhibitors, citalopram and fluoxetine, were studied on the presynaptic actions of 5-HT in the cat isolated nictitating membrane and in the guinea-pig isolated atria. Frequency-effect curves to nerve stimulation and concentration-response curves to noradrenaline (NA) were performed in both preparations. The facilitation that 0.1 microM 5-HT causes on the contractile responses to nerve stimulation of the nictitating membrane of the cat was not potentiated but entirely prevented by both 0.01 microM citalopram and 1.0 microM fluoxetine. On the other hand the diminution that 1.0 microM 5-HT evokes on the chronotropic responses to nerve stimulation of guinea-pig isolated atria was not modified at all by 0.1 and 1.0 microM fluoxetine and only partially prevented by 10.0 microM fluoxetine and by 0.001 microM, 0.01 microM and 0.1 microM citalopram. This latter effect of citalopram was unrelated to the concentration employed. The 5-HT uptake inhibitors did not modify per se either the responses to nerve stimulation or the sensitivity to exogenous NA in both tissues studied. In addition, the 5-HT uptake inhibitors did not interfere with the contractile responses caused by 5-HT in the cat isolated nictitating membrane. Taken together, these observations might indicate a pharmacological rather than a physiological role for the effects of 5-HT in guinea-pig isolated atria and cat nictitating membranes. It is concluded that the 5-HT uptake inhibitors do not potentiate but even antagonize the presynaptic effects of 5-HT. Our results also show that 5-HT uptake inhibitors are more effective to interfere with the facilitation rather than with the inhibition that 5-HT causes on sympathetic responses.

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citalopram Celexa
The effects of citalopram (Lu 10-171) on the serotonin (5-HT) uptake kinetics in platelets from endogenously depressed patients.

Beving H, Bjerkenstedt L, Malmgren R, Olsson P, Unge G.

The uptake kinetics of serotonin (5-HT) in platelets from eight patients with endogenous depression was determined in platelet rich plasma (PRP). From the uptake data the Scatchard correlation coefficient (r[S] ), Sips' index of heterogeneity (alpha), Km and Vmax (Lineweaver-Burk) were calculated. The measurements were performed before and after two weeks treatment with Citalopram, 1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)-5-phtalan carbonitrile (Lu 10-171), a selective 5-HT uptake inhibitor. After two weeks treatment with Citalopram (5, 25 or 50 mg/day) a lowered platelet count in whole blood and PRP was observed and none of the patients had a measurable 5-HT uptake for which kinetic parameters (Km and Vmax, Lineweaver-Burk) could be calculated. However, all the patients but one improved significantly in Global score.

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citalopram Celexa
Role of the serotonin uptake carrier in the neurochemical response to methamphetamine: effects of citalopram and chlorimipramine.

Schmidt CJ, Gibb JW.

The role of the serotonin uptake carrier in the methamphetamine-induced depression of serotonin synthesis was examined. In vivo, coadministration of citalopram or chlorimipramine with methamphetamine blocked the irreversible depression of tryptophan hydroxylase activity observed in the neostriatum and cerebral cortex after repeated administration of high doses of methamphetamine. The methamphetamine-induced reduction of neostriatal serotonin and 5-hydroxyindoleacetic acid was also attenuated by the two uptake inhibitors. In contrast, neither drug antagonized the depression of neostriatal tyrosine hydroxylase activity observed after methamphetamine administration. Citalopram also blocked the reversible inhibition of tryptophan hydroxylase activity observed after the acute administration of methamphetamine. In vitro, citalopram significantly inhibited methamphetamine-induced [3H]serotonin release from neostriatal slices. The results demonstrate that inhibitors of the serotonin uptake carrier can antagonize both the in vivo and in vitro effects of methamphetamine on serotonergic neurons. Furthermore, the methamphetamine-induced depression of serotonin synthesis is dependent upon a functional serotonin uptake system.

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citalopram Celexa
Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities.

Pawlowski L, Nowak G, Gorka Z, Mazela H.

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (greater than or equal to 0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
Kinetics of citalopram in elderly patients.

Fredericson Overo K, Toft B, Christophersen L, Gylding-Sabroe JP.

The kinetics of the antidepressant drug citalopram, a specific 5-HT uptake inhibitor, has been investigated in 11 elderly patients (age 73-90) and compared to previous data from younger patients and volunteers. The recorded steady state citalopram levels of 140-545 nM after a once-daily 20-mg dose were up to four times higher than expected from data in younger patients and volunteers. The biological half-life (1.5-3.75 days) and estimated systemic clearance (0.08-0.3 1/min) also differed from data in younger individuals (1.5 days and 0.4 1/min, respectively). Clearance values generally decreased with increasing age. Drug/metabolite ratios were higher in patients with the longest half-lives and lowest citalopram clearance, indicating reduced metabolic activity. No reduction in renal clearance was indicated by urine data, obtained for two of the patients. The study suggests that daily doses of 5-20 mg give approximately the same steady state plasma levels in elderly patients as doses of 40 mg in younger, and that this is due to reduced rates of metabolism in the elderly.

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