Prozac
Changes in sleep patterns by intralaminar thalamic microinjection of fluoxetine in rats.

Tsai LL, Tsai YF.

Department of Physiology, College of Medicine, National Taiwan University, Taipei, Republic of China.

Sleep patterns were investigated in rats by analysis of EEG recorded for 6 hours following fluoxetine or saline (control) microinjection into the centromedial intralaminar thalamus (CIT) at either 9:30 AM or 1:30 PM, 4 or 8 hours after lights on, respectively. The treatment of fluoxetine at 9:30 AM did not affect any sleep patterns. In contrast, fluoxetine significantly suppressed total paradoxical sleep (PS) time and the number of PS episodes during the second and third hour after administration at 1:30 PM. In addition, microinjection of fluoxetine produced an apparent enhancement of the duration of slow wave sleep (SWS) episodes and a small non-significant increase in total SWS time. On the other hand, no obvious changes in the basal sleep-wakefulness pattern were found between the two saline-treated control groups. These results indicate that CIT microinjection of fluoxetine at different time points acts differentially in sleep patterns and suggest that CIT may be one of the action sites for peripherally administered fluoxetine to alter sleep patterns.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8234539&dopt=Abstract fluoxetine Prozac



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Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study.

Hrdina PD, Vu TB.

Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.

This study was undertaken to investigate the effect of chronic treatment with fluoxetine, a selective serotonin uptake inhibitor used widely in the treatment of depression, on the distribution and density of 5-HT uptake sites, 5-HT2 receptors, and vesicular amine uptake sites in rat brain. Fluoxetine (10 mg/kg i.p.) was administered daily for 21 days. The density of 5-HT uptake sites labelled by [3H]paroxetine, 5-HT2 receptors labelled by [3H]ketanserin in presence of tetrabenazine and vesicular amine uptake sites labelled by [3H]ketanserin in the presence of mianserin were measured by quantitative autoradiography in 22 areas of rat brain, using coronal tissue sections. Chronic administration of fluoxetine produced significant increases in the density of 5-HT uptake sites in layers of frontoparietal cortex (by 32-43%), of striate cortex (by 55%), in CA1 field of hippocampus (by 111%) and in superior colliculus (by 20%). Fluoxetine treatment also resulted in upregulation of 5-HT2 receptors in layers of frontoparietal cortex (31-38%) and in CA2-3 fields of hippocampus (by 39%). The density of tetrabenazine-sensitive vesicular amine uptake sites in the caudate-putamen was also significantly increased (by 66%). The observed alterations in 5-HT uptake site and 5-HT2 receptor densities are likely a part of adaptive neuronal changes that occur after chronic administration of fluoxetine and may be related to the antidepressant effect of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8248854&dopt=Abstract fluoxetine Prozac



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Evaluation of the effect of fluoxetine on the formation of carbamazepine epoxide.

Gidal BE, Anderson GD, Seaton TL, Miyoshi HR, Wilenksy AJ.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle 98195.

Fluoxetine has been reported to increase carbamazepine (CBZ) plasma concentrations and cause adverse effects. CBZ-10, 11 epoxide (CBZE), the major metabolite of CBZ, contributes to the clinical effect and toxicity of CBZ. The objective of the present study was to investigate the effect of fluoxetine and its major metabolite, norfluoxetine, on CBZE formation in isolated perfused rat liver, in vitro human liver (n = 5) microsomes, and patients (n = 14), after either CBZ monotherapy or polytherapy with fluoxetine. In isolated perfused rat liver, there was no effect of fluoxetine (n = 8) or norfluoxetine (n = 6) on the formation clearance of CBZE (12.8 +/- 5.3 and 11.7 +/- 3.8 ml/min, respectively) or the intrinsic metabolic clearance of CBZ (6.6 +/- 2.7 and 6.3 +/- 1.8 ml/min, respectively). Studies on human liver microsomes confirmed that neither fluoxetine or norfluoxetine inhibited formation of CBZE until concentrations were > 20 times those found clinically. In support of this, there was no difference in the ratio of CBZE to CBZ plasma concentrations in patients also receiving fluoxetine when compared to patients on CBZ monotherapy; however, there was a trend toward a decrease in the apparent plasma clearance of CBZ. In conclusion, increased plasma concentrations of CBZ found when fluoxetine is added are not due to decreased formation of CBZE. Clinically, if fluoxetine causes an increase in CBZ levels, CBZE plasma concentrations will increase proportionately and contribute to the toxicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8249047&dopt=Abstract fluoxetine Prozac



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Fluoxetine prevents the disruptive effects of fenfluramine on differential-reinforcement-of-low-rate 72-second schedule performance.

Richards JB, Sabol KE, Seiden LS.

University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.

This study compared the effects of fenfluramine and fluoxetine on the differential-reinforcement-of-low-rate 72-s schedule of reinforcement. Fluoxetine, a clinically effective antidepressant, increases extracellular serotonin (5-HT) by blocking the uptake of 5-HT after release. Fenfluramine increases extracellular 5-HT through transporter-mediated release (although it also blocks 5-HT uptake). The following characteristics were identified. First, fenfluramine and fluoxetine had two different effects on the differential-reinforcement-of-low-rate 72-s schedule. Fluoxetine had an antidepressant-like effect by increasing reinforcement rate without disrupting the interresponse time distribution. Fenfluramine's effect on the differential-reinforcement-of-low-rate 72-s schedule was not antidepressant-like: it did not increase the reinforcement rate, whereas it did disrupt the interresponse time distribution. Second, when fluoxetine and fenfluramine were given in combination, fluoxetine prevented the disruptive effects of fenfluramine. This result is consistent with fluoxetine's ability to block fenfluramine-induced 5-HT release, and supports the argument that the uptake transporter mediates fenfluramine's effects on both 5-HT release and behavior. Putative behavioral mechanisms (waiting capacity and temporal discrimination) which may mediate the acute effects of fluoxetine are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8263788&dopt=Abstract fluoxetine Prozac



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Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion.

Walker PW, Cole JO, Gardner EA, Hughes AR, Johnston JA, Batey SR, Lineberry CG.

Department of Psychiatry, University of Tennessee, Memphis.

BACKGROUND: This study was conducted to determine the effect of bupropion on the sexual functioning of male and female outpatients who developed anorgasmia or delayed orgasm while receiving fluoxetine treatment for depression. METHOD: Thirty-nine patients who satisfied criteria for participation in the study discontinued fluoxetine treatment and entered a 2-week washout phase followed by an open 8-week bupropion treatment phase. Three parameters of sexual functioning were followed throughout the study: orgasm function, libido, and satisfaction with overall sexual functioning. Depression was also evaluated at each visit. RESULTS: All patients reported orgasm delay and/or failure at the time of fluoxetine discontinuation. Orgasm function, libido, and satisfaction with sexual functioning improved during the 2-week fluoxetine washout period and during the bupropion treatment phase. Ninety-four percent of patients (29/31) had complete or partial resolution of their orgasm dysfunction at the end of bupropion treatment, and 81% of patients (25/31) were "much" or "very much" more satisfied with their overall sexual functioning. Most patients entered the study with decreased libido on fluoxetine. Libido was "much" or "very much" increased for 81% of patients (25/31) at the end of the study. In addition, depression scores on the Hamilton Rating Scale for Depression and Clinical Global Impressions-Severity scale significantly improved during the bupropion treatment phase. Finally, bupropion was well tolerated by most patients. CONCLUSION: Bupropion may be an appropriate antidepressant for patients who develop sexual dysfunction during fluoxetine treatment or for whom sexual dysfunction is a concern.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8276736&dopt=Abstract fluoxetine Prozac



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Effects of triiodothyronine and fluoxetine on 5-HT1A and 5-HT1B autoreceptor activity in rat brain: regional differences.

Lifschytz T, Gur E, Lerer B, Newman ME.

Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

The thyroid hormone triiodothyronine (T3) augments and accelerates the effects of antidepressant drugs. Although the majority of studies showing this have used tricyclics, a few studies have shown similar effects with the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. In this study we investigated the effects of fluoxetine (5 mg/kg), T3 (20 microg/kg) and the combination of these drugs, each administered daily for 7 days, on serotonergic function in the rat brain, using in vivo microdialysis. Fluoxetine alone induced a trend towards desensitization of 5-HT1A autoreceptors as shown by a reduction in the effect of 8-OH-DPAT to lower 5-HT levels in frontal cortex, and desensitized 5-HT1B autoreceptors in frontal cortex. The combination of fluoxetine and T3 induced desensitization of 5-HT1B autoreceptors in hypothalamus. Since there is evidence linking hypothalamic function and depression, we suggest that this effect may partly account for the therapeutic efficacy of the combination of an SSRI and T3.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15589343&dopt=Abstract fluoxetine Prozac



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5-HT1A receptors are differentially involved in the anxiolytic- and antidepressant-like effects of 8-OH-DPAT and fluoxetine in the rat.

De Vry J, Schreiber R, Melon C, Dalmus M, Jentzsch KR.

CNS Research, Bayer HealthCare, Aprather Weg 18a, 42096 Wuppertal, Germany. Jean.DeVry Grunenthal.de

Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15589388&dopt=Abstract fluoxetine Prozac



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Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats.

Ceyhan M, Kayir H, Uzbay IT.

Psychopharmacology Research Unit, Department of Medical Pharmacology, Faculty of Medicine, Gulhane Military Medical Academy, Etlik, Ankara 06018, Turkey.

The effects of tianeptine and fluoxetine on pentylenetetrazole (PTZ)-induced seizures in rats were investigated. Female Wistar rats (172-278 g) were used in the study. Tianeptine (1.25, 2.5, 5, 10 and 20 mg/kg) and fluoxetine (2.5, 5, 10 and 20 mg/kg) or saline were injected to rats intraperitoneally 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ administrations, latency and intensity of the PTZ-induced seizures was recorded and scored, respectively. Fluoxetine (2.5-20 mg/kg) did not produce any significant difference in latency and intensity of the PTZ-induced seizures. Although tianeptine (1.25-20 mg/kg) also did not affect the latency time, it produced significant attenuations in the intensity of the seizures. Tianeptine did not cause any significant change in the locomotor activity of the rats. The results of this preliminary study suggest that tianeptine but not fluoxetine has some inhibitory effects on PTZ-induced seizures in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15589568&dopt=Abstract fluoxetine Prozac