citalopram escitalopram Lexapro
Hormone responses to citalopram in abstinent alcohol dependent subjects.

Gotjen D, Szabo Z, Lee S, Wand G.

Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

BACKGROUND: The integrity of serotonin neurotransmission may be important in reducing risk for alcoholism and in preventing relapse to alcohol dependence. There are several lines of evidence suggesting that alcohol dependent persons have an altered and/or injured serotonin system. The purpose of this study was to examine ACTH, cortisol, and prolactin responses to the selective serotonin reuptake inhibitor (SSRI), citalopram, as a function of personal or family history of alcohol dependence in a group of abstinent alcohol dependent men. METHODS: Twelve healthy, abstinent male participants who met diagnostic criteria for a history of alcohol dependence but not for other Axis I disorders were included in the study (mean years abstinent, 3.5 +/- 3.7; mean years of dependent drinking, 15.2 +/- 6.9). Fourteen healthy volunteers served as control subjects. Controls did not meet the DSM-IV diagnostic criteria for any Axis I disorders and history of drug or alcohol abuse or dependence. All subjects were also characterized by the presence or absence of family history of alcoholism validated by collateral interviews. RESULTS: ACTH responses to citalopram were minimally faster in abstinent alcohol dependent men compared to controls. However, cortisol and prolactin responses to citalopram did not differ by personal or family history of alcohol dependence. There was no correlation between hormone responses and the duration of abstinence from alcohol; between hormone responses and the years of dependent drinking and between hormone responses and NEO Personality Inventory scores. CONCLUSION: By probing the functional capacity of the serotonin system with citalopram, we did not detect physiologically relevant hormone differences between abstinent alcohol dependent men and controls.

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citalopram escitalopram Lexapro
Effects of acute citalopram treatment on the methamphetamine-induced locomotor activity.

Kameda K, Tanaka T, Miura J, Kusumi I, Koyama T.

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

1. Previously the authors have shown that acute citalopram treatment increased the dopamine D2 receptor expression in rat brain striatum (Kameda et al., 2000). In the present study, the authors attempted to determine whether these effects of citalopram influence the methamphetamine-induced locomotor activity. 2. The pretreatment with a single administration of citalopram (10 mg/kg, i.p.) resulted in the significant enhancement of the locomoter activity induced by methamphetamine treatment (1 mg/kg, i.p.). The enhancement was observed 30 min, 12 hours, 24 hours, but not 7 days after withdrawal of citalopram administration. 3. Then the authors determined the methamphetamine concentration in rat brain striatum by gas chromatography-mass spectrometry (GC-MS) The results showed that the concentration of methamphetamine wars significantly higher in the rats 24 hours, and also 7 days after withdrawal of citalopram administration, compared to the control rats. 4. These results emphasized the involvement of the high methamphetamine concentration, caused by the pretreatment with citalopram, in the enhancement of the methamphetamine-induced locomotor activity. However high methamphetamine concentration alone could not account for this enhancement, since the high concentration of methamphetamine observed 7 days after withdrawal of citalopram administration did not appear to enhance the methamphetamine-induced locomotor activity. Another mechanism through which the pretreatment with citalopram enhanced the methamphetamine-induced locomotor activity, such as the increased expression of the dopamine D2 receptors, could not be excluded.

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citalopram escitalopram Lexapro
Species-scanning mutagenesis of the serotonin transporter reveals residues essential in selective, high-affinity recognition of antidepressants.

Mortensen OV, Kristensen AS, Wiborg O.

Laboratory of Molecular Neurobiology, Department of Biological Psychiatry, Psychiatric University Hospital, Risskov, Denmark.

The serotonin transporter (SERT) is a high-affinity sodium/chloride-dependent neurotransmitter transporter responsible for reuptake of serotonin from the extracellular space. SERT is a selective target of several clinically important antidepressants. In a cross-species analysis comparing human and bovine SERTs, the kinetic parameters for serotonin uptake were found to be similar, however, the pharmacological profiles of the two transporters differ. Following transient expression in COS-1 cells, IC(50) values were determined for several antidepressants and psychostimulants. The potencies of the antidepressants citalopram, fluoxetine, paroxetine and imipramine were several-fold higher at hSERT compared with bSERT. No species selectivity was observed for the antidepressants fluvoxamine, and sertraline or for the psychostimulants cocaine, the cocaine analogue beta-carbomethoxy-3beta-(4-iodophenyl)tropane, or for 3,4-methylenedioxymethamphetamine (MDMA). Analysis of six hSERT/bSERT chimeras and subsequent species-scanning mutagenesis of each isoform revealed methionine-180, tyrosine-495, and phenylalanine-513 to be responsible for the increase in citalopram and paroxetine potencies at hSERT and methionine-180 and phenylalanine-513 to confer species selectivity at hSERT for fluoxetine and imipramine. Results were obtained by doing the forward, bovine to human, mutations and confirmed by doing the reverse mutations. Citalopram analogues were used to define the roles of methionine-180, tyrosine-495, and phenylalanine-513 and to reveal molecular interactions with individual functional groups of citalopram. We suggest that methionine-180 interacts with the heterocyclic nucleus of citalopram or stabilizes the binding pocket and phenylalanine-513 to be a steric blocker of antidepressant recognition.

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Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Jensen JB, Mork A, Mikkelsen JD.

Department of Neurobiology, H. Lundbeck A/S, Copenhagen, Denmark. jbj azign.com

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

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Effect of citalopram and buspirone on the antinociceptive action of analgesic drugs.

Pakulska W, Czarnecka E.

Department of Pharmacodynamics, Medical University of Lodz, Poland.

The influence of citalopram (20 mg/kg i.p.) and buspirone (3 mg/kg i.p.) on analgesic effects of morphine (10 mg/kg i.p.), metamizole (500 mg/kg i.p.) and indomethacin (10 mg/kg) was studied with tail-flick and hot-plate tests on mice. The research studies were further conducted with multiple (14 days) drug dosage. The results indicate that citalopram and buspirone decrease analgesic effects of morphine, metamizole and indomethacin. This mode of action is more pronounced in case of a single dose than after multiple doses.

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Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue.

Angulo J, Peiro C, Sanchez-Ferrer CF, Gabancho S, Cuevas P, Gupta S, Saenz de Tejada I.

Fundacion para la Investigacion y el Desarrollo en Andrologia, Department de Investigacion, Hospital Ramon y Cajal, Madrid, Spain.

Increased incidence of impotence is associated with some selective serotonin-reuptake-inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency-related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, N(G)-nitro-L-arginine (0.3 mg x kg(-1)). Acute or chronic (2 weeks) paroxetine-treatment (10 mg x kg(-1)) reduced ICP-responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression.

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[11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats.

Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S.

PET Centre, Centre for Addiction and Mental Health and University of Toronto, Toronto, Ontario M5T 1R8, Canada. nginovart camhpet.on.ca

The in vivo pharmacological profile of [(11)C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomography (PET). The in vivo distribution of [(11)C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, respectively. [(11)C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [(11)C]-DASB binding to the SERT. Two cats were each examined using PET and [(11)C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1) fluoxetine, and 2) citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (approximately 90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, respectively, than those of fluoxetine and norfluoxetine. In addition, studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [(11)C]-DASB for binding on the SERT. These studies indicate that [(11)C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels. Copyright 2002 Wiley-Liss, Inc.

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