J Pharmacol Exp Ther. 1999 Oct;291(1):1-6.
Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3.

Choi JS, Hahn SJ, Rhie DJ, Yoon SH, Jo YH, Kim MS.

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

The effects of fluoxetine (Prozac), a widely used antidepressant drug, on Kv1.3 stably expressed in Chinese hamster ovary cells were examined using the whole-cell and excised inside-out configurations of the patch-clamp technique. In whole-cell recordings, fluoxetine accelerated the decay rate of inactivation of Kv1.3 and thus decreased the current amplitude at the end of the pulse in a concentration-dependent manner with an IC(50) value of 5.9 microM. The inhibition displayed a weak voltage dependence, increasing at more positive potentials. Neither the activation nor the steady-state inactivation curve was affected by fluoxetine. In addition, fluoxetine reduced the tail current amplitude and slowed the deactivation of the tail current, resulting in a crossover phenomenon. When applied to the internal side of the membrane in inside-out recordings, the inhibition by fluoxetine was much faster and more potent with an IC(50) value of 1.7 microM compared with whole-cell recordings. Norfluoxetine, the major metabolite of fluoxetine, also inhibited Kv1.3 in a concentration-dependent manner (IC(50) = 1.4 microM) in whole-cell recordings. To check whether the fluoxetine-induced inhibition demonstrated in cloned Kv1.3 could also be observed in native T lymphocytes, the effects of fluoxetine were investigated on human T lymphocytes. Fluoxetine also inhibited outward K(+) current in human T lymphocytes. Our results indicate that fluoxetine produced a concentration- and voltage-dependent inhibition of Kv1.3 that can be interpreted as an open channel block and that a binding site for fluoxetine is more accessible from the intracellular side.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10490879&dopt=Abstract fluoxetine

princeton.edu

The ability of pindolol to enhance the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) is generally attributed to a blockade of the feedback inhibition of serotonergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit activity of serotonergic dorsal raphe nucleus neurons in awake cats after acute treatment with the SSRI fluoxetine. The effects of pindolol were compared with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635), a selective 5-HT(1A) receptor antagonist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i. v.) decreased neuronal firing rates to approximately 50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (+/-)-pindolol (0.1-5 mg/kg i.v.) failed to reverse the neuronal inhibition produced by either dose of fluoxetine. In addition to lacking efficacy as an antagonist in these experiments, (+/-)-pindolol produced an additional decrease in neuronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in restoring neuronal activity after fluoxetine. In contrast, systemic administration of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) at low doses (0.025 mg/kg i.v.), and further elevated the firing rate of these neurons above prefluoxetine baseline levels. Overall, these results indicate that pindolol, unlike WAY-100635, lacks apprec

iupui.edu

The clinically important antidepressant fluoxetine is established as a selective serotonin reuptake inhibitor. This study demonstrates that fluoxetine also interacts with the GABA(A) receptor complex. At concentrations above 10 microM fluoxetine inhibited the binding of both [3H]GABA (IC50 = 2 mM) and [3H]flunitrazepam (IC50 = 132 microM) to the GABA(A) receptor complex in brain cortical membranes. Low fluoxetine concentrations (1 nM) enhanced GABA-stimulated Cl- uptake by a rat cerebral cortical vesicular preparation. At higher concentrations (100 microM and 1 mM), however, fluoxetine inhibited GABA-stimulated Cl- uptake, an effect related to a reduction in Emax. These observations might assist in an explanation of the basis of the antidepressant action of fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10492522&dopt=Abstract fluoxetine

sage.scripps.edu

RATIONALE: Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized. OBJECTIVES: The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs. METHODS: A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle. RESULTS: Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1-5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretrea

bagnex.synthelabo.fr

It has been previously reported that Wistar-Kyoto (WKY) rats may be useful in the study of the biological mechanisms involved in stress-related disorders. In the present study, WKY were treated acutely or chronically (one daily i.p. injection for 22-24 days) with the selective 5-HT reuptake inhibitor and clinically effective antidepressant and anxiolytic fluoxetine (5 and 20 mg/kg) and exposed to the forced swimming test (FST) and to the elevated plus-maze (EPM) at different times postinjection (30, 60, min or 24 h). In the FST, WKY failed to respond to fluoxetine, regardless of treatment. In the EPM, acute fluoxetine (20 mg/kg) produced anxiolytic-like effects when animals were tested 24 h, but not 30 min after drug administration. Positive effects in the EPM were evident on both conventional (open-arm activity) and ethological (risk assessment) measures in the absence of effect on activity measures (total and closed-arm entries). No evidence for anxiolytic-like activity was observed following chronic fluoxetine. These results indicate that WKY rats are resistant to fluoxetine treatment in the FST, while their behavior may be modified in the EPM when animals received a single fluoxetine challenge 24 h before testing. Overall, these findings provided little evidence that WKY rats may represent a valid model of stress-related disorders.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10497947&dopt=Abstract fluoxetine




Br J Pharmacol. 1999 Sep;128(1):21-6.
Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats.

Malone DT, Taylor DA.

Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), 381 Royal Parade, Parkville 3052, Victoria, Australia.

1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurred after i.v. administration of 0.5 - 5 mg kg-1 Delta9-THC when compared with vehicle (n=5 - 8, P<0.05). Maximum increases, ranging from 42.1+/-5. 4% to 97.4+/-5.9% (means+/-s.e.mean) of basal levels occurred 20 min after Delta9-THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg-1 i.p.). 3. Pretreatment with fluoxetine (10 mg kg-1 i.p.) abolished the Delta9-THC-induced DA release. Fluoxetine 10 mg kg-1 i.p. administered 40 min after Delta9-THC had no significant effect on Delta9-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 microM) 40 min after Delta9-THC significantly potentiated the Delta9-THC-induced DA release (n=6 - 8, P<0.05). 4. These results suggest that DA release induced by Delta9-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Delta9-THC. Fluoxetine induces an acute increase in extracellular 5-HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Delta9-THC-induced DA release. The potentiation of Delta9-THC-induced DA release by fluoxetine perf




J Affect Disord. 1999 Sep;55(1):11-7.
Fluoxetine efficacy in menopausal women with and without estrogen replacement.

Amsterdam J, Garcia-Espana F, Fawcett J, Quitkin F, Reimherr F, Rosenbaum J, Beasley C.

Depression Research Unit, University of Pennsylvania Medical Center, Philadelphia 19104, USA.

A gradual decline in estrogen levels after the age of 40 may contribute to a higher rate of depression in women over 45 years of age. Estrogen replacement therapy (ERT) has been shown to produce cognitive and mood-enhancing effects in women and may facilitate antidepressant activity. METHODS: We examined the efficacy rates in women on ERT > or = 45 years (n = 40) compared to women > or = 45 years not on ERT (n = 132) and to women < 45 years (n = 396) and to men (n = 262) with major depression during fluoxetine 20 mg daily up to 8 weeks. Remitters with a HAM-D17 score < or = 7 from week 9 to 12 were then treated up to 1-year in a placebo-controlled, relapse-prevention trial. RESULTS: Efficacy rates were similar in women > or = 45 years on ERT when compared to women > or = 45 years taking fluoxetine alone, and when compared to women < 45 years and men taking fluoxetine. A Kaplan-Meier survival analysis in fluoxetine responders treated up to 26 weeks showed a somewhat greater relapse rate in women > or = 45 years taking ERT compared to other treatment groups (P < 0.06). LIMITATIONS: This study was retrospective nature and ERT was given in an uncontrolled fashion: 63% of women received estrogen alone while 37% also took intermittent progesterone. Other variables include the absence of hormonal documentation of menopausal status, no direct assessment of ERT compliance and the use of fixed-dose fluoxetine 20 mg daily. CONCLUSION: In contrast to prior reports suggesting that ERT may facilitate antidepressant activity, we observed similar efficacy in depressed women > or = 45 years taking fluoxetine plus ERT compared to those taking fluoxetine alone.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10512601&dopt=Abstract fluoxetine [

wanadoo.fr

RATIONALE: Many biological abnormalities have been found in obsessive-compulsive disorder (OCD). The circadian rhythm investigations of different clinical and biological parameters may provide a comparison with depression. Fluoxetine is one of the efficient drugs in alleviating symptoms of OCD. The effect of fluoxetine can highlight some clues to the neurotransmitter alterations in the disorder. OBJECTIVE: The present study investigated clinical and biological circadian modifications in OCD patients during a fluoxetine treatment. METHODS: Daily clinical symptoms, and circadian rhythms of axillary temperature, plasma cortisol and plasma melatonin were assessed in eight patients suffering from OCD. These parameters were compared in the same patients, before and after an 8-week fluoxetine treatment period. RESULTS: A therapeutic effect of fluoxetine was obtained. No significant differences were observed either in daily clinical variations or in biological circadian rhythms measured before and after treatment. CONCLUSION: The therapeutic efficacy of fluoxetine was not related to the biological parameters assessed.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10541726&dopt=Abstract fluoxetine




Mol Cell Biochem. 1999 Sep;199(1-2):103-9.
Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity.

Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC.

Department of Physics and Chemistry, School of Pharmaceutical Sciences, University of Sao Paulo, Brasil.

The effects of fluoxetine on the oxidative phosphorylation of mitochondria isolated from rat brain and on the kinetic properties of submitochondrial particle F1F0-ATPase were evaluated. The state 3 respiration rate supported by pyruvate + malate, succinate, or ascorbate + tetramethyl-p-phenylenediamine (TMPD) was substantially decreased by fluoxetine. The IC50 for pyruvate + malate oxidation was approximately 0.15 mM and the pattern of inhibition was the typical one of the electron-transport inhibitors, in that the drug inhibited both ADP- and carbonyl cyanide m-chlorophenylhydrazone (CCCP)-stimulated respirations and the former inhibition was not released by the uncoupler. Fluoxetine also decreased the activity of submitochondrial particle F1F0-ATPase (IC50 approximately 0.08 mM) even though K0.5 and activity of Triton X-100 solubilized enzyme were not changed substantially. As a consequence of these effects, fluoxetine decreased the rate of ATP synthesis and depressed the phosphorylation potential of mitochondria. Incubation of mitochondria or submitochondrial particles with fluoxetine under the conditions of respiration or F1F0-ATPase assays, respectively, caused a dose-dependent enhancement of 1-anilino-8-naphthalene sulfonate (ANS) fluorescence. These results show that fluoxetine indirectly and nonspecifically affects electron transport and F1F0)-ATPase activity inhibiting oxidative phosphorylation in isolated rat brain mitochondria. They suggest, in addition, that these effects are mediated by the drug interference with the physical state of lipid bilayer of inner mitochondrial membrane.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10544958&dopt=Abstract fluoxetine [PubMed