Neuropsychopharmacology. 2004 Apr;29(4):694-704.
Chronic fluoxetine treatment partly attenuates the long-term anxiety and depressive symptoms induced by MDMA ('Ecstasy') in rats.

Thompson MR, Li KM, Clemens KJ, Gurtman CG, Hunt GE, Cornish JL, McGregor IS.

School of Psychology, University of Sydney, NSW, Australia.

Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 x 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9-12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5-week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA ex

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The anti-inflammatory activity of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was studied on the carrageenan-induced paw inflammation in the rat. Fluoxetine (10-60 mg kg(-1)) given intraperitoneally (i.p.) 30 min before carrageenan, displayed marked anti-inflammatory activity, inhibiting paw oedema by 38.6-77.7% at 2 h post-carrageenan. Fluoxetine administered at time of carrageenan injection or 30 min after carrageenan challenge, markedly inhibited the paw oedema response. Rats administered daily fluoxetine (20 mg kg(-1), i.p.) showed significantly decreased inflammatory response to subplantar carrageenan when examined on the 5th and 14th day of fluoxetine injection. Fluoxetine (10 or 20 mg kg(-1), i.p.) co-administered with indomethacin (IND) (20 mg kg(-1), i.p.), celecoxib (10 mg kg(-1), i.p.) or rofecoxib (4.5 mg kg(-1), i.p.) before carrageenan reduced the anti-oedema effect of indomethacin or celecoxib, but had additive effect to that of rofecoxib. The anti-oedema effects of fluoxetine and melatonin or the tricyclic antidepressant imipramine were additive. In contrast, administration of both fluoxetine and the heterocyclic antidepressant trazodone had no greater anti-inflammatory effect than fluoxetine alone. The anti-oedema effect of fluoxetine was partially suppressed by the opioid antagonist naloxone (4 mg kg(-1), i.p.). Fluoxetine (360 or 720 microg per paw) given into the rat paw with carrageenan reduced the oedema response by 25.4 and 35.3% 4 h post-carrageenan, respectively. It is suggested that fluoxetine alone or co-administered with either imipramine or melatonin would be of benefit in the sitting of neuropathic or inflammatory pain conditions. Both the serotonergic and the opioid systems are likely to be in




Neuroreport. 2003 Dec 19;14(18):2451-5.
Fluoxetine blocks cloned neuronal A-type K+ channels Kv1.4.

Choi BH, Choi JS, Ahn HS, Kim MJ, Rhie DJ, Yoon SH, Min DS, Jo YH, Kim MS, Hahn SJ.

Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, Socho-gu, Seoul.

The effects of fluoxetine were studied on cloned K+ channel Kv1.4 stably expressed in Chinese hamster ovary (CHO) cells using the whole-cell configuration of the patch-clamp technique. Extracellular application of various concentrations of fluoxetine inhibited the amplitude of the peak current of Kv1.4 and accelerated its inactivation time course in a concentration-dependent manner. Thus, fluoxetine decreased Kv1.4 (the integral of the outward current) in a concentration-dependent manner; the IC50 was 33.1 +/- 2.5 microM. The inhibitory effect of fluoxetine was time-dependent. The apparent association (k) and dissociation (l) rate constants measured at +40 mV were 3.5 +/- 0.7 microM-1s-1 and 132.5 +/- 13.3 s-1, respectively. The Kd (= l/k) was 37.9 microM, which was close to the value obtained from the concentration-response curve. The block produced by fluoxetine increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. The fluoxetine block was constant at more depolarized potentials, suggesting that the block by fluoxetine was not voltage dependent. Our data indicate that fluoxetine blocks Kv1.4 channels by preferentially binding to open state.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14663209&dopt=Abstract fluoxetine




Neuropharmacology. 2004 Feb;46(2):232-42.
Brain region and dose effects of an olanzapine/fluoxetine combination on extracellular monoamine concentrations in the rat.

Koch S, Perry KW, Bymaster FP.

Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.

Clinical studies of patients with treatment-resistant depression have shown that combined treatment with fluoxetine and olanzapine rapidly and significantly improved depressive symptoms. The present study used in vivo microdialysis to investigate the brain regional and dose effects of these drugs on extracellular monoamine concentrations in the rat prefrontal cortex, hypothalamus, nucleus accumbens and striatum. In the prefrontal cortex, the olanzapine/fluoxetine combination (3/10 mg/kg, respectively) increased catecholamine concentrations to a significantly greater extent than either drug alone (dopamine mean+/-S.E.M. percent of baseline: olanzapine (120 +/- 12.4), fluoxetine (123 +/- 6.2), combination (185 +/- 8.8); norepinephrine: olanzapine (124 +/- 7.2), fluoxetine (126 +/- 5.0), combination (215 +/- 15.8)). The combination also increased serotonin concentrations to 156 +/- 11.0% of baseline, but to a lesser extent than fluoxetine alone (210 +/- 14.5%). Similar synergistic effects of the combination were observed in the hypothalamus, but not in the other regions studied. The dose response effects of the drugs alone and in combination were complex, but larger doses of the combinations produced greater monoamine concentration increases than smaller dose combinations.The effects of the olanzapine/fluoxetine combination are meaningful in prefrontal cortex and hypothalamus due to their hypothesized role in the etiology and pharmacotherapy of depression. The wide-ranging neurochemical effects of this drug combination may make it particularly useful as a treatment for complex, resistant depressions.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14680761&dopt=Abstract fluoxetine

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Several studies have suggested that testosterone has a role in nociception. Recently, we have shown that castration and flutamide, a testosterone antagonist, induce analgesia in the late phase of formalin test, which is related to increase of 5-HT levels in the dorsal horn of the lumbar spinal cord. The aim of the present study was to investigate the effect of fluoxetine, a selective serotonin reuptake inhibitor, on castration and flutamide-induced analgesia in order to further explore the role of 5-HT systems in such analgesia. Four weeks after castration, there was an analgesia in the late phase of formalin test, and this was potentiated by acute (0.32 mg kg(-1) ip) treatment of fluoxetine. Furthermore, coadministration of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) produced more antinociceptive effect than those animals receiving fluoxetine and flutamide alone. The analgesic effect of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) was abolished by pretreatment with 5,7-DHT (100 microg/rat it) and naloxone (2 mg kg(-1) ip). In summary, our data suggest that fluoxetine and flutamide have antinociceptive effects in tonic inflammatory pain through functional alteration of serotonergic systems, and their effects are potentiated by coadministration. The possible role of opioidergic system in their antinociceptive effect cannot be neglected.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724036&dopt=Abstract fluoxetine

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Onset of action is a key unmet need in the treatment of depression. However, very few preclinical models in which the effects of antidepressants can be shown are suitable for screening for onset. In this context, previous literature suggests that a slow onset of action of selective serotonin reuptake inhibitors (SSRIs) is observed in schedule-induced polydipsia (SIP). The current investigation was performed to determine the latency to reduce SIP of the SSRI, fluoxetine, and of two treatments known to facilitate 5-HT neurotransmission to a greater extent than an SSRI alone. These treatments included interaction studies for fluoxetine+the 5-HT(1A) antagonist, WAY 100635, and for fluoxetine+the 5-HT(1B) partial agonist, GR 127935. Food-restricted rats were trained on a fixed interval schedule with drinking water freely available. Once water intake was stable, rats were randomly assigned to vehicle of treatment groups. Daily treatment was continued for 3 (interaction studies) or 18 days (fluoxetine alone study). Fluoxetine significantly reduced SIP after 5-6 days of treatment, with the maximal effect evidenced after 8 days. WAY 100635 and GR 127935 accelerated the onset of action of fluoxetine, with significant effects observed on treatment day 1. These data suggest that SIP may be useful to assess the onset of action of serotonin enhancers.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724043&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 2004 Apr;173(1-2):153-9. Epub 2004 Jan 15.
Influence of fluoxetine on positive and negative affect in a clinic-based smoking cessation trial.

Cook JW, Spring B, McChargue DE, Borrelli B, Hitsman B, Niaura R, Keuthen NJ, Kristeller J.

Department of Psychology, 1007 West Harrison Avenue, 60607-7137, Chicago, IL, USA.

RATIONALE. Fluoxetine improves affect in clinical syndromes such as depression and premenstrual dysphoric disorder. Little is known about fluoxetine's influence on mood changes after quitting smoking, which often resemble sub-clinical depression. OBJECTIVES. The present study, a re-analysis of previously published data (Niaura et al. 2002), examined fluoxetine's effect on changes in negative and positive affect following quitting smoking. METHODS. Adult smokers ( n=175) without clinically significant depression were randomized on a double-blind basis to receive fluoxetine hydrochloride (30 or 60 mg daily) or placebo for 10 weeks in combination with cognitive-behavioral therapy (CBT) for smoking cessation. We postulated that fluoxetine would beneficially influence post-cessation changes in positive and negative affect. RESULTS. Mood change across treatment was analyzed using mixed linear modeling controlling for initial level of nicotine dependence, plasma fluoxetine metabolites, and change in cotinine (a nicotine metabolite) at each visit. Relative to placebo, those on 60 mg fluoxetine experienced an elevation in positive affect that increased across time [ t(526)=2.50, P=0.01], and a reduction in negative affect that returned to baseline across time [ t(524)=2.26, P=0.02]. There were no differences between 30 mg and placebo on changes in positive or negative affect. CONCLUSIONS. Results indicate that 60 mg of fluoxetine improves both positive and negative mood states after quitting smoking and that diminished positive affect may be an overlooked affective response to smoking cessation.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14727000&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 2004 Jan 22 [Epub ahead of print]
Fluoxetine, but not sertraline or citalopram, potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects.

Fletcher PJ, Sinyard J, Salsali M, Baker GB.

Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, M5T 1R8, Toronto, Ontario, Canada.

RATIONALE. The selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances some of the behavioural effects of cocaine, including locomotor stimulation. While this effect has often been interpreted as evidence for a serotonergic component to the behavioural effects of cocaine, direct evidence for this hypothesis is lacking. One alternative explanation is that fluoxetine, by inhibiting cytochrome P450 (CYP) enzymes, interferes with the metabolism of cocaine. OBJECTIVES. These experiments were undertaken to: 1) compare the effects of fluoxetine with those of two other SSRIs, sertraline and citalopram, on cocaine-induced locomotor activity, 2) examine the effects of fluoxetine on cocaine-stimulated locomotion in rats depleted of serotonin (5-hydroxytrptamine; 5-HT), and 3) determine the effect of fluoxetine on cocaine levels in the brain. METHODS. Locomotor activity was measured, using photocell based activity monitors, in rats habituated to those monitors. Depletion of 5-HT was achieved by injecting 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Cocaine levels in whole brain were measured using high-performance liquid chromatography with ultraviolet detection. RESULTS. In experiment 1, 5 mg/kg fluoxetine enhanced the ability of 10 and 15 mg/kg cocaine to increase locomotor activity. Neither citalopram nor sertraline (5 and 10 mg/kg) altered the stimulant effect of 10 mg/kg cocaine. Experiment 2 showed that this effect of fluoxetine was also apparent in rats with large and widespread depletion of brain 5-HT levels. The 5-HT depletion also failed to alter the response to cocaine itself. In experiment 3, brain levels of cocaine

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STUDY OBJECTIVE: To compare treatment adequacy in the management of depression during the acute and continuation phases between patients newly treated with venlafaxine extended release (XR) and those newly treated with fluoxetine. DESIGN: Retrospective observational analysis of pharmacy claims data. SETTING: Large California-based managed care organization. PATIENTS: A total of 11,298 patients newly prescribed venlafaxine XR or fluoxetine between January 1, 2000, and February 28, 2001, and continuously enrolled throughout the study, as well as a subset of 7430 patients who continued taking venlafaxine XR or fluoxetine during the follow-up period. MEASUREMENTS AND MAIN RESULTS: The Health Plan Employer Data and Information Set definition was used for continuous antidepressant treatment during the acute and continuation phases. Treatment adequacy was determined for those deemed continuous. Patients receiving within +/- 10% of the target dose for each drug (venlafaxine XR 75-150 mg, fluoxetine 20 mg) were defined as receiving an adequate dose. Logistic regression was used to evaluate venlafaxine XR versus fluoxetine on treatment adequacy, controlling for age, sex, physician specialty, and pharmacy benefit. The unadjusted adequacy rate for the venlafaxine XR-only group was 79% versus 57% for the fluoxetine-only group for 84 continuous days (p<0.0001) and 77% versus 52%, respectively, for 180 continuous days (p<0.0001). The adjusted odds ratios of achieving treatment adequacy with venlafaxine XR only versus that with fluoxetine only were 3.05 (95% confidence interval [CI] 2.65-3.52) for 84 continuous days and 3.57 (95% CI 3.00-4.24) for 180 continuous