citalopram Celexa
5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats.

Millan MJ, Girardon S, Dekeyne A.

Institut de Recherches Servier, Psychopharmacology Department, Paris, France.

Rats were trained on a fixed ratio 10, food-reinforced schedule to recognize a discriminative stimulus (DS) elicited by the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram (2.5 mg/kg, IP). The preferential, high efficacy agonist at 5-HT2C receptors, Ro60-0175, dose-dependently generalized to citalopram with an ED50 of 0.3 mg/kg, IP. Further, the selective 5-HT2C receptor antagonist, SB242,084, dose-dependently (ED50=0.1 mg/kg, IP) blocked the citalopram DS. These data suggest that 5-HT2C receptors are involved in the DS properties of the SSRI, citalopram, in rats. They do not, however, exclude a potential role of other 5-HT receptor types.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10229070&dopt=Abstract citalopram Celexa



citalopram Celexa
Serotonin innervation of Lurcher mutant mice: basic data and manipulation with a combination of amantadine, thiamine and L-tryptophan.

Le Marec N, Hebert C, Botez MI, Botez-Marquard T, Marchand L, Reader TA.

Centre for Research in Neurological Sciences, Department of Physiology, Faculty of Medicine, University of Montreal, CHUM--Hotel-Dieu Hospital, Quebec, Canada.

The Lurcher (Lc/+) mutant mouse is characterized by a considerable atrophy of the cerebellum due to a massive loss of cerebellar Purkinje and granule cells, as well as of neurons from the inferior olivary nucleus. In this study the effects of a therapeutic combination of amantadine, thiamine and L-tryptophan on the serotonin (5-HT) innervation was assessed in Lurcher mice by autoradiography, using [3H]citalopram to label 5-HT transporters. In wild type mice as well as in both saline-treated and drug-treated Lurcher mutants, [3H]citalopram binding remained unchanged in forebrain and brainstem regions. In the cerebellum, labelling of deep cerebellar nuclei (CBnuc) was about twofold higher than in the cortex (CBctx). In saline-treated Lurcher mutants compared to wild type mice, the densities of [3H]citalopram were 98% higher in CBctx, and 180% higher in CBnuc. In CBctx of drug-treated Lurcher mutants, transporter densities were 89% higher than in the wild type, but did not differ from the saline-treated Lurcher. In the CBnuc of the drug-treated Lurcher mutants, [3H]citalopram binding was 50% higher than in the saline-treated Lurcher group, and 320% higher than in wild type mice. The results show that 5-HT transporters, already upregulated in the CBnuc of Lurcher mutant mice, can be further increased by a pharmacological treatment, possibly altering the availability of 5-HT in some of its target areas.

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citalopram Celexa
[Mechanisms of action of antidepressants: new data from Escitalopram]

[Article in French]

Fabre V, Hamon M.

INSERM U288, Neuropsychopharmacologie, CHU Pitie-Salpetriere, 91, boulevard de l'Hopital, 75634 Paris cedex 13.

A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, weight gain, dry mouth, etc, mainly caused by their capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approximately 30% of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 weeks of treatment, like that observed with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addition, the potency of Escitalopram to inhibit serotonin reuptake (K(i)=2,1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is especially relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such as fluoxetine) to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 weeks of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 weeks with any other antidepressant drug. These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is) > or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.

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citalopram Celexa
Comparison of the effects of the selective serotonin-reuptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats.

Maurel S, De Vry J, Schreiber R.

CNS Research, Bayer AG, Cologne, Germany.

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

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citalopram Celexa
Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in male rats.

Jensen JB, Jessop DS, Harbuz MS, Mork A, Sanchez C, Mikkelsen JD.

Department of Clinical Biochemistry, Bispebjerg Hospital, Copenhagen, Denmark. jej lundbeck.com

It is well established that the maximal therapeutic effect of selective serotonin reuptake inhibitors (SSRI) are achieved in depressive patients after several weeks of treatment, but the adaptive processes leading to the therapeutic effects are unclear. It has been shown that hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis in depressive patients is affected by long-term antidepressant treatment. These changes occur in association with the mood normalising effect, suggesting that antidepressants affect the HPA axis and this effect is associated with the therapeutic effect. Male Wistar rats were treated with the SSRI, citalopram, to investigate time-related changes in components that may be involved in the desensitization of the HPA axis. A single injection of citalopram (10 mg/kg, s.c.), increased the plasma levels of ACTH and corticosterone in a dose-dependent manner and increased the number of c-Fos containing cells in the hypothalamic paraventricular nucleus. A daily treatment with the same compound (10 mg/kg, s.c.) for 14 days decreased the expression of POMC mRNA ( approximately 40%). In addition, a blunted response to citalopram was observed in animals long-term treated with citalopram. Also CRF-stimulated cAMP accumulation in the pituitary was altered. In conclusion, acute citalopram activated the HPA-axis at the hypothalamic level and long-term citalopram treatment desensitized the HPA-axis at the pituitary level. These results support the hypothesis that the therapeutic effects of long-term antidepressant treatments reduce HPA axis responsiveness.

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citalopram Celexa
Synthesis and biological evaluation of novel carbon-11-labelled analogues of citalopram as potential radioligands for the serotonin transporter.

Madsen J, Merachtsaki P, Davoodpour P, Bergstrom M, Langstrom B, Andersen K, Thomsen C, Martiny L, Knudsen GM.

PET & Cyclotron Unit 3982, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. j.madsen rh.dk

Three serotonin reuptake inhibitors where the 5-cyano group in citalopram [1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1)] was replaced with a methyl, acetyl and piperidinyl carbonyl group, respectively, were synthesized. In a Stille reaction applying [(11)C]methyl iodide the labelled compound [5-methyl-(11)C][3-[1-(4-fluorophenyl)-5-methyl-1,3-dihydroisobenzofuran-1-yl]-propyl]-dimethylamine ([(11)C]-2) was synthesized in 60-90% radiochemical yield. [5-carbonyl-(11)C][1-[1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]-1-piperidin-1-yl-methanone] ([(11)C]-3) was synthesized in 62% radiochemical yield in a palladium mediated cross-coupling reaction utilizing [(11)C]carbon monoxide. The specific activity of [(11)C]-2 was highly dependent on whether the corresponding trimethyltin or tributyltin precursor was applied. In ex vivo rodent studies compound [(11)C]-2 exhibited a good blood-brain barrier (BBB) penetration whereas [(11)C]-3 did not. The brain distribution of [(11)C]-2 was investigated in a non-human primate using PET. There was a rapid uptake of radioactivity into the brain. Accumulation of the radiotracer was in agreement with the known distribution of serotonin transporters. The maximal thalamus to cerebellum ratio of 1.3 was reached after 85 min and the specific binding was partly blocked after pre-treatment with citalopram. Thus, [(11)C]-2 does not exhibit appropriate properties as radioligand for visualization of the serotonin transporter in vivo.

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citalopram Celexa
Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.

Apelqvist G, Wikell C, Hindfelt B, Bergqvist PB, Andersson G, Bengtsson F.

Institute of Laboratory Medicine, Department of Clinical Pharmacology, Lund University Hospital, Sweden.

RATIONALE: Latent or manifest chronic hepatic encephalopathy (HE) symptomatology often includes affective symptoms. It is therefore warranted to investigate the functional outcome of novel antidepressants when chronic HE prevails. OBJECTIVE: Portacaval shunt (PCS) in rats is a widely used experimental model for chronic HE, a neuropsychiatric syndrome accompanying liver dysfunction. HE is believed to arise from a primary alteration in neurotransmission in the CNS. PCS has been reported to increase the metabolism of serotonin in the brain, and thus the central serotonin nerve of PCS rats may contain more serotonin than normal. However, the functional relevance of this serotonergic alteration in terms of affecting behavioral performance of PCS rats has been only rarely studied. METHODS: Locomotor and rearing activities were recorded in PCS and sham-operated control rats. A single subcutaneous challenge with saline versus either the mixed serotonin/noradrenaline reuptake inhibitor venlafaxine (10 mg x kg(-1)) or the selective serotonin reuptake inhibitor citalopram (5 mg x kg(-1)) were performed. RESULTS: The PCS-saline injected rats showed reduced locomotor and rearing activity compared with sham-saline treated rats. While no significant differences could be observed following the venlafaxine challenge to controls, the PCS-venlafaxine challenged rats displayed reduced behavioral activity as compared to PCS-saline treated rats. The PCS-citalopram rats, however, displayed increased activity compared with the PCS-saline rats while, again, no effect of the citalopram challenge to controls was found. CONCLUSIONS: The present study show altered but opposite behavior in PCS rats, when challenged with either venlafaxine or citalopram, compared to PCS control rats. These findings therefore support the contention that caution should be advocated when CNS monoamine active drugs are used in liver-impaired subjects until better delineation of the combined pharmacodynamic and pharmacokinetic outcome for each such drug in this condition has been made.

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citalopram Celexa
Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium.

Rochat B, Baumann P, Audus KL.

Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.

Blood-brain barrier transport of the selective serotonin reuptake inhibitor and antidepressant, citalopram, was studied using monolayers of bovine brain microvessel endothelial cells (BMECs). This study provides for the first time, evidence of a transport mechanism for a selective serotonin reuptake inhibitor (SSRI). Carrier-mediated transport, efflux mechanisms, as well as inhibition of metabolizing enzymes of citalopram were investigated. Citalopram transport was saturable and temperature-dependent suggesting that passage of the drug across BMECs was mediated by a carrier mechanism. Since the apical to basolateral and basolateral to apical permeability coefficients were similar and cyclosporin A, a P-glycoprotein inhibitor, does not modify the transport of citalopram, it appeared that no active efflux systems were involved in this transport. Citalopram is only available as a racemic drug and its pharmacological effect resides mainly in the S-(+)-enantiomer. However, the passage of citalopram enantiomers across BMEC monolayers was not stereoselective. Finally, inhibition of the metabolizing enzymes of citalopram and monoamine oxidases did not modify the permeation of citalopram across BMECs. Collectively, our results suggested that citalopram crosses the blood-brain barrier via a non-stereoselective, bidirectional and symmetrical carrier-mediated mechanism without influences of active efflux mechanisms or monoamine oxidases. Copyright 1999 Elsevier Science B. V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10412001&dopt=Abstract citalopram Celexa