Eur J Pharmacol. 2002 May 17;443(1-3):99-104.
Improved efficacy of fluoxetine in increasing hippocampal 5-hydroxytryptamine outflow in 5-HT(1B) receptor knock-out mice.

Malagie I, David DJ, Jolliet P, Hen R, Bourin M, Gardier AM.

Laboratoire de Neuropharmacologie UPRES EAD MENRT, Faculte de Pharmacie IFR-ISIT Institut de Signalisation et d'Innovation Therapeutique, Universite Paris-Sud, Tour D1 2eme etage 5 rue 1-B.Clement, 92296, Chatenay-Malabry cedex, France.

To test for the contribution of the 5-HT(1B) receptor subtype in mediating the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), we used intracerebral in vivo microdialysis in awake, freely moving 5-HT(1B) receptor knock-out mice. We show that a single systemic administration of fluoxetine (1, 5 or 10 mg/kg, i.p.) increased extracellular serotonin levels [5-HT](ext) in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, fluoxetine, at the three doses studied, induced a larger increase in [5-HT](ext) in knock-out than in wild-type mice. In the frontal cortex, the effect of fluoxetine did not differ between the two genotypes. The region-dependent response to fluoxetine described here in mutants confirms data we recently reported for another SSRI, paroxetine. These data suggest that 5-HT(1B) autoreceptors limit the effects of selective serotonin reuptake inhibitors on dialysate 5-HT levels at serotonergic nerve terminals located mainly in the ventral hippocampus. Alternative mechanisms, e.g., changes in 5-HT transporter and/or 5-HT(1A) receptor density in 5-HT(1B) receptor knock-out mice could also explain these findings.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12044798&dopt=Abstract fluoxetine




Obes Res. 2002 Jun;10(6):532-40.
Effects of fluoxetine administration on neuropeptide y and orexins in obese zucker rat hypothalamus.

Gutierrez A, Saracibar G, Casis L, Echevarria E, Rodriguez VM, Macarulla MT, Abecia LC, Portillo MP.

Department of Physiology, Faculty of Pharmacy, University of the Basque Country, Paseo de la Universidad 7, 01006 Vitoria, Spain.

OBJECTIVE: The aim of this work was to study the potential involvement of neuropeptide Y (NPY) and orexins in the anorexigenic mechanism of fluoxetine in obese Zucker rats, assessing the effects of chronic fluoxetine treatment on NPY and orexin immunostaining in several hypothalamic regions. RESEARCH METHODS AND PROCEDURES: Male obese Zucker (fa/fa) rats were administered fluoxetine (10 mg/kg intraperitoneally) daily for 2 weeks. The control group was administered 0.9% NaCl solution. Carcass composition was assessed using the official methods of the Association of Official Analytical Chemists. To test the potential thermogenic effect of fluoxetine administration, total body oxygen consumption was measured daily for 60 minutes before fluoxetine or saline injection and for 30 minutes after drug or saline injection. Hypothalamic arcuate and paraventricular nuclei, and the lateral hypothalamic area were immunostained for NPY, orexin A, and orexin B. Commercial kits were used for serum determinations. RESULTS: Chronic fluoxetine administration in obese Zucker rats generated a reduction in body weight gain, food intake, adipocyte size, fat mass, and body protein. A decrease in NPY immunostaining in the paraventricular nucleus, without changes in the arcuate, was observed. However, no changes were observed in the number of neural cells immunostained for orexin A or orexin B in the lateral hypothalamic area. DISCUSSION: Due to the hyperphagic effect of NPY in the paraventricular nucleus, these results suggest that NPY, but not orexins, could be involved in the anorexigenic effect of fluoxetine in obese Zucker rats.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055&dopt=Abstract

unica.it

The effects of acute and chronic administration of fluoxetine on the basal and stress-induced increases in cerebrocortical and plasma concentrations of allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-TH PROG) and tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) were compared with those of mirtazapine, an antidepressant that (unlike fluoxetine) is not a selective serotonin reuptake inhibitor. A single injection (20 mg/kg i.p.) of fluoxetine or mirtazapine resulted in significant increases in the cerebrocortical and plasma concentrations of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC. In contrast, long-term administration (10 mg/kg i.p., once daily for 2 weeks) of fluoxetine, but not that of mirtazapine, induced marked decreases in the cortical and plasma concentrations of these neuroactive steroids. Chronic treatment with fluoxetine, however, did not inhibit the increases in the cortical and plasma concentrations of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC induced by acute foot-shock stress. In contrast, chronic treatment with mirtazapine prevented or significantly reduced the stress-induced increases in neurosteroid concentrations in the cerebral cortex and plasma, respectively. These results show that mirtazapine, similar to fluoxetine, initially increases the cortical concentration of neuroactive steroids; however, chronic administration of this drug modulates the plasma and brain availability of these hormones in a manner distinct from that of fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12095071&dopt=Abstract fluoxetine

gsk.com

Clinical augmentation strategies have shown that some improvement in antidepressant efficacy can be achieved by combining the beta-adrenergic/serotonin (5-HT)1A/1B receptor antagonist (+/-)pindolol with a selective serotonin reuptake inhibitor (SSRI). This has lead to the hypothesis that a combination of a 5-HT1A receptor antagonist with an SSRI will lead to a faster onset of antidepressant action. Although there is a significant accumulation of acute preclinical data supporting this rationale, until recently, there have been no investigations examining the chronic effects of combining an SSRI with a 5-HT1A receptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT1A receptor antagonist WAY-100635 (1 mg/kg b.i.d.), on serotonergic neurotransmission in the frontal cortex using in-vivo microdialysis. Following chronic administration of fluoxetine +/- WAY-100635, functional changes in serotonergic neurotransmission, as well as 5-HT1A autoreceptors, were assessed by administering fluoxetine or (+/-) 8-hydroxy-2-(di-n-propylamino)tetralin [(+/-) 8-OH-DPAT] 24 h after the last chronic dose. Chronic administration of WAY-100635 alone produced no detectable change in the functional status of the 5-HT1A receptor. However, fluoxetine alone produced a time-dependent adaptation in serotonergic transmission such that fluoxetine (acutely administered on day 15) was able to produce a two-fold increase in extracellular 5-HT levels but the decrease in response to 8-OH-DPAT was completely attenuated. These data indicate that the fluoxetine-induced adaptation was mediated by desensitization of the 5-HT1A receptor. WAY-100635 given chronically in combinatio




Brain Res. 2002 Jul 12;943(2):206-15.
Evidence for serotonergic modulation of progesterone-induced hyperphagia, depression and algesia in female mice.

Kaur G, Kulkarni SK.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India.

The acute administration of the neurosteroid precursor, progesterone (10 mg/kg, s.c.) produced significant hyperphagia in female mice as observed at 0.5-, 1-, 2- and 3-h time intervals. At this dose progesterone also produced significant increase in immobility period duration in Porsolt's forced swim test and nociceptive response in hot-plate and tail-flick tests. Treatment with direct (quipazine, 5 mg/kg, i.p.) and indirect (fluoxetine, 10 mg/kg, i.p.) acting serotonergic agents per se produced significant hypophagia, decrease in immobility period and induced analgesic effect in hot-plate and tail-flick test. Further, treatment with both fluoxetine (10 mg/kg, i.p.) and quipazine (5 mg/kg, i.p.) significantly reversed progesterone-induced hyperphagia, depression and algesia in the female mice. Pretreatment with seganserin, a 5-HT(2) receptor antagonist (2 mg/kg, i.p.) significantly reversed fluoxetine and quipazine-induced antidepressant and analgesic effects. Seganserin reversed quipazine-induced hypophagia but in a replicate study it failed to reverse fluoxetine-induced hypophagia. Further, seganserin, 2 mg/kg, i.p., significantly reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced hyperphagia, depression and algesia in hot-plate test. Seganserin also reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced algesia in hot-plate test. These data suggest that the modulation of progesterone-induced effects by these serotonergic agents possibly involve 5-HT(2) receptor mechanisms. Further, the study underscores the use of serotonergic agents for the treatment of eating and affective disorders caused by the regular changes or disturbances of ovarian




J Pharmacol Exp Ther. 2002 Feb;300(2):543-8.
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.

Thomas D, Gut B, Wendt-Nordahl G, Kiehn J.

Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.

Fluoxetine is a commonly prescribed antidepressant compound. Its action is primarily attributed to selective inhibition of the reuptake of serotonin (5-hydroxytryptamine) in the central nervous system. Although this group of antidepressant drugs is generally believed to cause fewer proarrhythmic side effects compared with tricyclic antidepressants, serious concerns have been raised by case reports of tachycardia and syncopes associated with fluoxetine treatment. To determine the electrophysiological basis for the arrhythmogenic potential of fluoxetine, we investigated the effects of this drug on cloned human ether-a-go-go-related gene (HERG) potassium channels heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. We found that fluoxetine blocked HERG channels with an IC(50) value of 3.1 microM. Inhibition occurred fast to open channels with very slow unbinding kinetics. Analysis of the voltage dependence of block revealed loss of inhibition at membrane potentials greater than 40 mV, indicating that channel inactivation prevented block by fluoxetine. No pronounced changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or inactivation time constant could be observed, and block was not frequency-dependent. This is the first study demonstrating that HERG potassium channels are blocked by the selective serotonin reuptake inhibitor fluoxetine. We conclude that HERG current inhibition might be an explanation for the arrhythmogenic side effects of this drug.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11805215&dopt=Abstract fluoxetine

lumc.edu

Although women constitute the majority of patients who receive treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, most animal studies of SSRIs are conducted on males. The present study investigated whether long-term treatment of cycling female rats with fluoxetine alters their estrous cycle and the sensitivity of hypothalamic serotonin (5-HT) 5-HT(1A) and 5-HT(2A) receptor systems. Adult female rats received daily injections of fluoxetine (10 mg/kg, i.p.) for three consecutive estrous cycles (15.2+/-0.2 days) with the first injection beginning on metestrus (when circulating estrogen levels are low and stable). Fluoxetine did not alter basal plasma estradiol levels at metestrus, nor did it alter the pattern of estrous cyclicity. Rats treated with fluoxetine showed a loss in body weight. On the morning of metestrus of the fourth cycle (18 h after the last fluoxetine injection), the rats were injected with a sub-maximal dose of the 5-HT(1A) agonist (+/-)-8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT, 50 MICRO/kg, s.c.) or a maximal dose of the 5-HT(2A) agonist [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] (DOI). Plasma levels of oxytocin, ACTH and corticosterone were measured as peripheral indicators of hypothalamic 5-HT(1A) and 5-HT(2A) receptor sensitivity. Injecting 8-OH-DPAT to saline pretreated rats produced a significant increase in plasma oxytocin (299%), ACTH (1456%) and corticosterone (170%) levels but not in plasma prolactin or renin concentrations. Greater increases in plasma levels of these hormones




Encephale. 2002 Jul-Aug;28(4):350-5.
[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]

[Article in French]

Owens JM, Knight DL, Nemeroff CB.

University school of Medicine. Dept of Psychiatry and Behavorial sciences, 1639 Pierce drive, suite 4000 WMRB, Atlanta GA 30322, USA.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonine reuptake ihibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (Ki=1,1 and 1,4 nmol/L, respectively). escitalopram was the most serotonin transporter-selective compound tested and was approximately 30 fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (Ki=64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed. (Biol Psychiatry 2001; 50: 345-350 " 2001 Society of Biological Psychiatry).

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12232544&dopt=Abstract fluoxetine




Ther Drug Monit. 2002 Oct;24(5):616-27.
Plasma concentrations of the enantiomers of fluoxetine and norfluoxetine: sources of variability and preliminary observations on relations with clinical response.

Jannuzzi G, Gatti G, Magni P, Spina E, Pacifici R, Zuccaro P, Torta R, Guarneri L, Perucca E.

Clinical Pharmacology Unit and University of Pavia, Italy.

Factors affecting the plasma concentrations of the R- and S-enantiomers of fluoxetine and norfluoxetine were investigated in 131 adult patients receiving long-term fluoxetine, of 10 to 60 mg/d (mean, 24 +/- 10 mg/d). Plasma concentration values (geometric means, CI 95%) in these patients were 186 (156, 223) nmol/L for S-fluoxetine, 67 (58, 77) nmol/L for R-fluoxetine, 247 (212, 287) nmol/L for S-norfluoxetine, and 118 (102, 137) nmol/L for R-norfluoxetine. The difference between the concentrations of the respective R- and S-enantiomers was statistically significant ( P< 0.0001) for both the parent drug and the demethylated metabolite. A significant correlation was found between the concentrations of each enantiomer and the prescribed daily dosage (r = 0.44, P< 0.0001 for S-fluoxetine; r = 0.48, P < 0.0001 for R-fluoxetine; r = 0.36, < 0.0001 for S-norfluoxetine; r = 0.32, P = 0.0003 for R-norfluoxetine), but the variability in concentration at any given dosage was considerable. When an iterative model based on multiple polynomial regressions was applied to determine the potential contributions of dosage, age, gender, body weight, and concomitant medication to the variability in the plasma concentration of the enantiomers, dosage was consistently found to provide the greatest predictive value. The predictive value of the model could be consistently improved when concentrations of other enantiomers were included as covariates. Of 58 patients with depressive symptoms for whom evaluation of clinical response (CGI scale) was available, 33 (57%) responded favorably to treatment. The plasma levels of individual enantiomers and of the ac