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Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: possible Ca(2+)-channel inhibition.

Stauderman KA, Gandhi VC, Jones DJ.

Marion Merrell Dow Research Institute, Cincinnati, OH 45215.

Fluoxetine, a selective 5-HT uptake inhibitor, inhibited 15 mM K(+)-induced [3H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations greater than 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K+ used to depolarize the synaptosomes and the concentration of external Ca2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [3H]5-HT release induced by the Ca(2+)-ionophore A 23187 or Ca(2+)-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K(+)-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca2+ channels and Ca2+ entry. Whereas fluoxetine and paroxetine inhibited binding of [3H]nitrendipine to the dihydropyridine-sensitive L-type Ca2+ channel, the less selective uptake inhibitors did not alter binding. The dihydropyridine antagonist nimodipine partially blocked fluoxetine-induced inhibition of release. Moreover enhanced K(+)-stimulated release due to the dihydropyridine agonist Bay K 8644 was reversed by fluoxetine. Fluoxetine also inhibited the K(+)-induced increase in intracellular free Ca2+ in fura-2 loaded synaptosomes. These data are consistent with the suggestion that fluoxetine inhibits K(+)-induced [3H]5-HT release by antagonizing voltage-dependent Ca2+ entry into nerve terminals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1608295&dopt=Abstract fluoxetine Prozac



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Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline.

Lee MD, Clifton PG.

Laboratory of Experimental Psychology, University of Sussex, Brighton, UK.

Experiment 1 showed that the reduction of intake produced by 5 or 10 mg/kg fluoxetine in rats eating either a solid or a liquid meal was partially antagonised by 1 mg/kg of the 5HT1/5HT2 antagonist metergoline but not by 1 mg/kg of the 5HT2 antagonist ketanserin. Experiment 2 examined the meal patterning of rats given 5 mg/kg fluoxetine and 1 mg/kg metergoline. Fluoxetine alone increased the latency to feed, reduced meal size and shifted the inter-pellet interval (IPI) distribution to the right. Metergoline alone had little immediate effect on food intake or other feeding parameters but partially reversed the reduction of food intake produced by fluoxetine. There was a complete reversal of the increased latency to feed and a partial reversal of the depression of meal size. However, the rightward shift of the IPI distribution caused by fluoxetine, which indicated a depression of feeding rate, was more pronounced after combined treatment. We conclude that fluoxetine reduces food intake by enhancing satiety through a serotonergic dependent mechanism but reduces feeding rate through a separate mechanism, whose neurochemical basis remains to be established.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1615137&dopt=Abstract fluoxetine Prozac



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Effects of fluoxetine or D-fenfluramine on serotonin release from, and levels in, rat frontal cortex.

Sarkissian CF, Wurtman RJ, Morse AN, Gleason R.

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.

Using in vivo microdialysis of frontal cortex in anesthetized rats, as well as analysis of frontal cortex homogenates, we examined the effects of chronic administration of fluoxetine (30 mg/kg, i.p.) or D-fenfluramine (7.5 mg/kg, i.p.), administered daily for 3 days, on serotonin and 5-HIAA levels a day later. Measurements were also taken after 3-, 7- , and 21-day recovery periods. Neither chronic fluoxetine nor D-fenfluramine changed basal serotonin release. Both treatments, however, transiently decreased the release of serotonin evoked by an acute dose of D-fenfluramine (10 mg/kg, i.p.). Release initially was completely suppressed in fluoxetine-pretreated animals but returned to normal by the 21st day of washout; following D-fenfluramine pretreatment, normal release was attained by the 7th day of washout. Both fluoxetine and D-fenfluramine transiently decreased 5-HIAA levels in the dialysates and tissues. Both drugs also caused prolonged changes in frontal cortex serotonin levels, D-fenfluramine lowering them but fluoxetine elevating them. These results suggest that, at comparable dosage levels relative to their ED50s, fluoxetine and D-fenfluramine cause comparable reversible effects on brain serotonin release. The drugs also cause prolonged but opposite changes in brain serotonin levels, probably reflecting differences in the extents to which they or their principal metabolites release serotonin and block its reuptake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1704283&dopt=Abstract fluoxetine Prozac



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Persistent blockade of potassium-evoked serotonin release from rat frontocortical terminals after fluoxetine administration.

Gardier AM, Wurtman RJ.

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.

We examined 5-HT and 5-HIAA release from frontal cortex evoked by high potassium chloride concentrations in rats pretreated for 3 days with high doses of the 5-HT uptake blocker fluoxetine or of dexfenfluramine, which both releases 5-HT and blocks its reuptake. The standard fluoxetine dose (30 mg/kg i.p.) was about 4 times the drug's ED50 in producing a serotonin-related behavioral effect, anorexia, while the dexfenfluramine dose (7.5 mg/kg i.p.) was about 6 times its ED50. These high doses were chosen in order to elucidate the mechanism by which similar doses of fluoxetine and dexfenfluramine had been found to produce long-term changes in serotonin dynamics. Fluoxetine decreased the basal release of both compounds; dexfenfluramine decreased basal 5-HIAA efflux without affecting the release of 5-HT release. Potassium-evoked 5-HT release was unchanged after dexfenfluramine pretreatment but was suppressed by fluoxetine doses as low as 7.5 mg per kg per day. Basal release of 5-HT and 5-HIAA returned to normal after 7 days of fluoxetine pretreatment, but evoked release continued to be suppressed. These data suggest that long-term changes in brain serotonin dynamics after high doses of dexfenfluramine or fluoxetine are related to the drug's mechanisms of action, specifically their blockade of 5-HT reuptake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1711396&dopt=Abstract fluoxetine Prozac



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Role of norfluoxetine in the inhibition of desipramine metabolism and in the inhibition of serotonin uptake after fluoxetine administration to rats.

Fuller RW, Snoddy HD.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1715593&dopt=Abstract fluoxetine Prozac



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Increased sensitivity of the serotonergic system during the breeding season in free-living American tree sparrows.

Sperry TS, Moore IT, Meddle SL, Benowitz-Fredericks ZM, Wingfield JC.

Department of Biology, University of Washington, Box 351800, Seattle, WA 98195, USA. tsperry u.washington.edu

In order to understand the physiological role of serotonin in regulating aggressive behaviour it is important to understand how this neuromodulator acts within the context of a naturally fluctuating social and physical environment. To accomplish this, we examined the effect of the selective serotonin reuptake inhibitor fluoxetine during the breeding season in free-living male American tree sparrows (Spizella arborea) in Northern Alaska. During this time period males are maximally aggressive towards territorial intruders. Male, territorial sparrows were injected with either vehicle or a 10 mg/kg dose of fluoxetine. One hour later, aggression was measured using a simulated territorial intrusion. Depending upon when birds were sampled, the aggression scores for vehicle and fluoxetine treatments were grouped according to the number of days after territorial behaviour was initiated. The three groups were: early, days 1-5; middle, days 6-10; and late, days 11-15. There was a significant overall difference between groups (F(5,36)=5.18, P<0.0015). Post hoc analysis demonstrated that the level of aggression did not differ between the three groups of saline injected birds. However, fluoxetine injected birds showed a time dependent decrease in aggression. When compared to control birds the middle and late fluoxetine groups had significantly less aggression. Furthermore, the late group of fluoxetine treated birds were significantly less aggressive than the early group of fluoxetine birds. This demonstrates that free-living male ATSPs show a rapid change in their behavioural response to fluoxetine across the first 2 weeks of the breeding season. The rapidity of the change in responsiveness suggests a dynamic sensitivity of the serotonergic system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15617778&dopt=Abstract fluoxetine Prozac



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The effect of fluoxetine in a model of chemically induced seizures--behavioral and immunocytochemical study.

Zienowicz M, Wislowska A, Lehner M, Taracha E, Skorzewska A, Maciejak P, Plaznik A.

Department of Experimental and Clinical Pharmacology, Warsaw Medical University, 26/28 Krakowskie Przedmiescie Street, 00-927 Warsaw, Poland.

The aim of this study was to examine the effects of acute fluoxetine treatment on pentylenetetrazol-induced convulsions in order to shape a model of seizures associated with treatment with antidepressants in rats. Moreover, the putative role of the hippocampal formation in this respect was investigated with the help of c-fos immuncytochemistry to mark local neuronal activity. It was found that fluoxetine (10.0 mg/kg, i.p.) enhanced the proconvulsive effect of pentylenetetrazol (50.0 mg/kg, i.p.), and simultaneously inhibited pentylenetetrazol-stimulated c-Fos expression in some areas of the hippocampus. Fluoxetine pretreatment did not alter pentylenetetrazol brain concentration indicating that this phenomenon was not related to the pharmacokinetic interaction. It is suggested that inhibition by fluoxetine of some neuronal populations contributing to the local feedback mechanism controlling excessive epileptiform discharges within the hippocampus might lead to an increase in epileptic activity. The reported in the present paper fluoxetine versus pentylenetetrazol interaction may, therefore, serve as a model of seizures associated with treatment with antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15619548&dopt=Abstract fluoxetine Prozac



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Increased carbamazepine plasma concentrations after fluoxetine coadministration.

Grimsley SR, Jann MW, Carter JG, D'Mello AP, D'Souza MJ.

Department of Pharmacy Practice, Mercer University School of Pharmacy, Atlanta, GA 30312.

The interaction between fluoxetine and carbamazepine was investigated in six normal, healthy male volunteers (aged 23 to 40 years). Subjects were given carbamazepine, 400 mg every morning, for 3 weeks. Venous carbamazepine blood samples were obtained at baseline and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the morning dose. Fluoxetine, 20 mg every morning, was then coadministered with carbamazepine for 7 days. Venous carbamazepine blood samples were again obtained as described. Carbamazepine and carbamazepine-10,11-epoxide (CBZE) were assayed by HPLC. Addition of fluoxetine resulted in a significant increase in the area under the concentration-time curve of carbamazepine (105.93 +/- 18.05 micrograms/ml.hr versus 134.97 +/- 12.15 micrograms/ml.hr; t = 3.284; df = 5; p = 0.022) and CBZE (11.6 +/- 1.93 micrograms/ml.hr versus 15.2 +/- 2.4 micrograms/ml.hr; t = 2.805; df = 5; p = 0.038). Both oral and intrinsic clearance of carbamazepine was decreased significantly on fluoxetine addition (3.87 +/- 0.68 L/hr versus 2.98 +/- 0.26 L/hr; t = 3.025; df = 5; p = 0.029 and 17.90 +/- 4.9 L/hr versus 11.92 +/- 1.4 L/hr; t = 3.037; df = 5; p = 0.029, respectively). No significant changes were determined for fraction of absorbed dose, volume of distribution, absorption rate constant, and elimination rate constant. These findings suggest that fluoxetine can inhibit the metabolism of carbamazepine. Careful monitoring of patients is recommended when these two drugs are coadministered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1855347&dopt=Abstract fluoxetine Prozac