Cell Signal. 1998 Nov;10(10):721-6.
Fluoxetine action on murine T-lymphocyte proliferation: participation of PKC activation and calcium mobilisation.

Edgar VA, Genaro AM, Cremaschi G, Sterin-Borda L.

Centro De Estudios Farmacologicos y Botanicos, Consejo Nacional de Investigaciones Cientificas y Tecnicas de la Republica Argentina (CONICET), Buenos Aires.

The present study was undertaken to analyse the effect of fluoxetine upon murine T-lymphocyte proliferation. We found that fluoxetine exerted a dual effect, which depended on the degree of lymphocyte activation: at mitogenic concentration (2 microg/mL) of concavalin A (Con A), we observed an inhibitory effect on cellular proliferation, whereas, on submitogenic Con A concentration (1 microg/mL), fluoxetine stimulated the cellular response. Given these facts, we studied PKC activation and calcium mobilisation in both stimulatory and inhibitory effects of fluoxetine on T-cell proliferation. We observed that fluoxetine increased PKC translocation obtained with 1 microg/mL Con A concentration, whereas PKC was degraded when 2 microg/mL was used. This mechanism is thought to be mediated by calcium mobilisation. According to our results, fluoxetine seemed to modulate calcium influx, which, in turn, would influence PKC translocation, modulating the immune response.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884023&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 1998 Dec;140(4):496-502.
Stimulus properties of fluvoxamine in a conditioned taste aversion procedure.

Gommans J, Bouwknecht JA, Hijzen TH, Berendsen HH, Broekkamp CL, Maes RA, Olivier B.

Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, The Netherlands.

A conditioned taste aversion (CTA) procedure in mice was used to investigate the stimulus effects of the serotonin reuptake inhibitors (SSRIs) fluvoxamine and fluoxetine. Fluvoxamine elicited a reliable CTA (ED50 = 24 mg/kg, SC) and a number of drugs were tested as pre-exposure drugs. Pre-exposure to the serotonin (5-HT)1A receptor agonists flesinoxan and +/- -8-hydroxy-dipropylaminotetralin (8-OH-DPAT) prevented the CTA induced by fluvoxamine (50 mg/kg, SC). Pre-exposure with the 5-HT2C receptor agonist MK 212 [6-chloro-2(1-piperazinyl)pyrazine] partially prevented the fluvoxamine-induced CTA, pre-exposure with the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] did not prevent the CTA induced by fluvoxamine. Flesinoxan pre-exposure also prevented the taste aversion induced by fluoxetine (10 mg/kg, SC) completely. This contrasts previous results obtained with fluoxetine, where was found that its stimulus is primarily mediated by 5-HT2C, and to a lesser degree by 5-HT1A receptors. Therefore, we compared the two SSRIs directly. Pre-exposure to fluvoxamine prevented the fluoxetine-induced CTA, whereas pre-exposure to fluoxetine only partially prevented the fluvoxamine-induced CTA. We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and, based primarily on the cross-comparison tests, that the two SSRIs have somewhat different stimulus properties.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888626&dopt=Abstract fluoxetine




Br J Clin Pharmacol. 1999 Feb;47(2):211-7.
Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people.

Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R.

Department of Health Care of the Elderly, Princess Margaret Hospital, Christchurch, New Zealand.

AIMS: To establish the incidence, time course and risk factors of hyponatraemia complicating treatment with fluoxetine or paroxetine in an elderly population. METHODS: Retrospective descriptive and case control study in an inpatient/outpatient assessment and rehabilitation service for people aged 65 years and over. Fourteen elderly patients with hyponatraemia complicating treatment with fluoxetine or paroxetine, matched with 56 controls drawn from 845 patients treated with fluoxetine or paroxetine over 3.5 years. No other SSRI antidepressants were used over the study period. RESULTS: The incidence of hyponatraemia was 4.7/1000 people treated/year (6.3/1000 for fluoxetine and 3.5/1000 for paroxetine). Hyponatraemia was detected at a median 13.5 (mean 18.6, range 4-64) days after commencing the drug. Mean (95% confidence intervals) body weights were lower in cases at 53.0 (95% CI 46.5-59.5) kg compared with controls at 64.5 (95% CI 60.1-68.4) kg (P<0.01). 71% of cases were women compared with 45% of controls (P=0.07) but the effect of gender was confounded by body weight. There were trends for cases to be older (odds ratio 1.10: 95% CI 0.99, 1.23) and lighter (odds ratio 0.92, 95% CI 0.86, 0.99). CONCLUSIONS: Approximately 1 in 200 elderly people treated per year with fluoxetine or paroxetine developed complicating hyponatraemia. Low body weight was a particular risk factor. Most cases occurred within 3 weeks of treatment.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10190657&dopt=Abstract fluoxetine




Acta Physiol Pharmacol Ther Latinoam. 1998;48(4):191-7.
Fluoxetine action upon human T lymphocyte proliferation.

Ayelli Edgar V, Genaro AM, Cremaschi GA, Sterin Borda L.

Centro de Estudios Farmacologicos y Botanicos (CEFYBO), Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Buenos Aires, Argentina.

The purpose of this study was to analyze the effect of fluoxetine upon human T lymphocyte proliferation, and to assess the early signals elicited after T cell triggering and cAMP formation. Blood samples from normal human volunteers were drawn from venipuncture and T cells were cultured in the presence or absence of Concanavalin A (Con A) and fluoxetine. Protein Kinase C (PKC) levels and cyclic adenosine monophosphate (cAMP) formation were also measured. Fluoxetine exerted dual effect, depending on the degree of lymphocyte activation: at mitogenic concentrations of Con A (2 micrograms/ml), we observed an inhibitory effect on cellular proliferation. This inhibitory effect involves PKC degradation and cAMP formation. On the other hand, when submitogenic Con A concentrations (1 microgram/ml) were used, fluoxetine stimulated the cellular response and increased PKC translocation. The participation of extracellular calcium mobilization could be involved in these mechanisms. According to our results, fluoxetine seems to modulate calcium influx which, in turn, would influence PKC translocation, thus modulating the immune response through a mechanism that could be involving cAMP participation.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9914808&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1999 Feb;288(2):561-7.
Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins.

Raap DK, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois 60153, USA.

Long-term exposure to fluoxetine produces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)1A receptors, indicated by a substantial inhibition of the 5-HT1A receptor-mediated stimulation of oxytocin and adrenocorticotropic hormone (ACTH) secretion. The present study investigated the time course and mechanism of this desensitization after discontinuation of fluoxetine administration. Male rats were injected with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days and were challenged with a 5-HT1A agonist, [8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) 50 microg/kg, s.c.] 2, 4, 7, 14, 28, or 60 days post-treatment. In control animals, 8-OH-DPAT significantly increased (approximately 15-fold) plasma levels of oxytocin and ACTH. At 2 days post-treatment, oxytocin and ACTH responses to 8-OH-DPAT were reduced by 74% and 68%, respectively. During further withdrawal from fluoxetine, there was a gradual increase in the oxytocin response toward control levels. However, even 60 days after discontinuation of fluoxetine, the oxytocin response was still significantly reduced by 26% compared with controls. In contrast, the suppressed ACTH response to 8-OH-DPAT (a less-sensitive indicator of desensitization) gradually returned to control levels by day 14 of withdrawal from fluoxetine. Interestingly, the sustained reductions in the hormone responses occurred in the absence of reductions in Gz or Gi protein levels in the hypothalamus. Furthermore, this desensitization was sustained in the absence of detectable levels of fluoxetine and no




Am J Physiol. 1999 Feb;276(2 Pt 1):L213-9.
Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology.

Reeve HL, Nelson DP, Archer SL, Weir EK.

Department of Physiology, University of Alberta, Edmonton, Canada T6G 2R7.

The anorexic agents dexfenfluramine and fenfluramine plus phentermine have been associated with outbreaks of pulmonary hypertension. The fenfluramines release serotonin and reduce serotonin reuptake in neurons. They also inhibit potassium current (IK), causing membrane potential depolarization in pulmonary arterial smooth muscle cells. The recent withdrawal of the fenfluramines has led to the use of fluoxetine and phentermine as an alternative anorexic combination. Because fluoxetine and venlafaxine reduce serotonin reuptake, we compared the effects of these agents with those of phentermine and dexfenfluramine on pulmonary arterial pressure, IK, and membrane potential. Fluoxetine, venlafaxine, and phentermine caused minimal increases in pulmonary arterial pressure at concentrations < 100 microM but did cause a dose-dependent inhibition of IK. The order of potency for inhibition of IK at +50 mV was fluoxetine > dexfenfluramine = venlafaxine > phentermine. Despite the inhibitory effect on IK at more positive membrane potentials, fluoxetine, venlafaxine, and phentermine, in contrast to dexfenfluramine, had minimal effects on the cell resting membrane potential (all at a concentration of 100 microM). However, application of 100 microM fluoxetine to cells that had been depolarized to -30 mV by current injection elicited a further depolarization of >18 mV. These results suggest that fluoxetine, venlafaxine, and phentermine do not inhibit IK at the resting membrane potential. Consequently, they may present less risk of inducing pulmonary hypertension than the fenfluramines, at least by mechanisms involving membrane depolarization.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9950882&dopt=Abstract fluoxetine

rohcg.on.ca

OBJECTIVE: To determine the efficacy of substituting moclobemide, a reversible monoamine oxidase-A inhibitor, for fluoxetine to reverse fluoxetine-induced sexual dysfunction in patients with depression. DESIGN: Prospective open trial. SETTING: Outpatient treatment. PARTICIPANTS: Five patients with depressive disorder who experienced sexual side effects during treatment with standard doses of fluoxetine (20 to 40 mg per day). INTERVENTION: Discontinuation of fluoxetine and replacement with moclobemide (300 to 600 mg per day) after a 2-week washout period. OUTCOME MEASURES: Libido, orgasmic function (in women) or erectile and ejaculatory function (in men), and overall improvement in sexual function during a follow-up period of 2 months to 3 years. RESULTS: Among patients receiving fluoxetine questioned about sexual side effects, 4 (1 man and 3 women) had treatment-related diminished libido with poor orgasmic response or partial erectile failure, and 1 female patient had enhanced sexual desire with intense clitoral stimulation. In all patients, sexual disturbances resolved completely after a 2-week washout period and a switch to treatment with moclobemide. Moclobemide was well tolerated. The antidepressant effect of moclobemide was comparable to that of fluoxetine. CONCLUSIONS: Moclobemide may be preferred as a treatment for depression in patients with fluoxetine-induced sexual dysfunction.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9987207&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1999 Apr;62(4):695-701.
Chronic fluoxetine in tests of anxiety in rat lines selectively bred for differential 5-HT1A receptor function.

File SE, Ouagazzal AM, Gonzalez LE, Overstreet DH.

Psychopharmacology Research Unit, Neuroscience Research Centre, GKT School of Biomedical Sciences, King's College London, UK.

Selective breeding for high and low sensitivity to the hypothermic response induced by the 5-HT1A receptor agonist 8- OH-DPAT has established two lines of rat (HDS and LDS, respectively) whose behavior differs in a model of depression and in the social interaction test of anxiety. The HDS line has a higher level of anxiety and, furthermore, does not display the usual anxiogenic response to intrahippocampal administration of 8-OH-DPAT. It was therefore hypothesized that this line of rat might be a useful model of high trait anxiety with a susceptibility to depression. We thus investigated whether chronic treatment with fluoxetine would result in an anxiolytic effect in the social interaction test in the LDS and HDS lines of rat. In both lines, acute fluoxetine (10 mg/kg) produced an anxiogenic effect in the social interaction test; when rats were tested 24 h after 14 days of fluoxetine treatment there were no anxiolytic effects in either line. In the social interaction test, chronic fluoxetine treatment did not change either the anxiogenic effect of 8-OH-DPAT (100 ng) injected bilaterally into the dorsal hippocampus in the LDS line or the lack of response in the HDS line. In the elevated plus-maze, chronic fluoxetine treatment resulted in a significant anxiogenic effect in the HDS line, but was without effect in the LDS line. Intrahippocampal 8-OH-DPAT was without effect in the plus-maze in either line. These results suggest that chronic treatment with fluoxetine did not modify the hippocampal 5-HT1A receptor in either line. The anxiogenic effects observed in the plus-maze in the HDS line after chronic fluoxetine might relate to line differences in 5-HT1A receptors in




Neuroreport. 1999 Feb 25;10(3):553-5.
Effects of acute and chronic fluoxetine treatment of CRH-induced anxiety.

To CT, Anheuer ZE, Bagdy G.

Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Budapest, Hungary.

The effects of acute and chronic fluoxetine treatment on anxiogenic effect of corticotropin-releasing hormone (CRH) were studied in the social interaction test in male Sprague-Dawley rats. Injection of CRH (100 ng, i.c.v.), fluoxetine (5 mg/kg, i.p.) or their combination had significant anxiogenic effects (decrease in total interaction time and increase in self-grooming) in the social interaction test. The effects of CRH and fluoxetine in combination were not additive. Fluoxetine, but not CRH significantly inhibited locomotor activity. After chronic fluoxetine treatment (5 mg/kg/day, 21 days) the acute anxiogenic effects of either CRH or fluoxetine were abolished. Our studies provide evidence for a 5-HT/CRH interaction in the regulation of anxiety.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10208588&dopt=Abstract fluoxetine