Arch Med Res. 2001 May-Jun;32(3):193-6.
Additive effect of clonidine and fluoxetine on apomorphine-induced aggressive behavior in adult male Wistar rats.

Skrebuhhova-Malmros T, Allikmets L, Matto V.

Department of Pharmacology, University of Tartu, Tartu, Estonia.

BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to be superior in its antiaggressive properties as compared with other antidepressants. The objective of the study was to investigate whether the effect of a minimal effective dose of fluoxetine could be potentiated by the alpha2-adrenergic agonist clonidine. METHODS: Vehicle (1.0 mL/kg), clonidine (0.1 mg/kg), fluoxetine (10 mg/kg), and their combination [clonidine (0.1 mg/kg) plus fluoxetine (10 mg/kg)] were injected into apomorphine-pretreated (1.0 mg/kg, once daily during 12 days) aggressive adult male Wistar rats. RESULTS: Repeated apomorphine treatment induced a gradual development of aggressive behavior. Combined clonidine and fluoxetine treatment attenuated the intensity of aggressive behavior, while these drugs alone had only a weak tendency toward reduction of aggression. Latency before the first attack was unchanged. CONCLUSIONS: Our experiments confirm that combined clonidine and fluoxetine treatment elicits an additive antiaggressive effect on apomorphine-induced aggressive behavior in rats.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11395183&dopt=Abstract fluoxetine




Synapse. 2000 Dec 15;38(4):471-6.
Fluoxetine increases the anorectic and long-term dopamine-depleting effects of phentermine.

Callahan BT, Yuan J, Ricaurte GA.

Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.

The anorectic drug phentermine produces dose-related toxic effects on brain dopamine (DA) neurons in animals. Until recently, phentermine was widely used in combination with fenfluramine for purposes of appetite suppression and weight loss. With the recent withdrawal of fenfluramine from the market, many people have begun combining phentermine with fluoxetine, a serotonin reuptake inhibitor which also produces mild anorectic effects. Fluoxetine, in addition to inhibiting serotonin reuptake, inhibits hepatic mixed function oxidase, which plays an important role in the metabolic degradation of amphetamines. The purpose of the present study was to assess the effects of fluoxetine on the anorectic and DA neurotoxic effects of phentermine in mice. Phentermine, in combination with fluoxetine, produced greater reductions in food intake and body weight than phentermine alone. The phentermine/fluoxetine combination also produced greater long-term reductions in brain DA levels than phentermine alone, likely reflecting greater DA neurotoxicity of the drug combination. Brain concentrations of phentermine were also found to be higher in animals pretreated with fluoxetine. These findings indicate that fluoxetine potentiates both the anorectic and DA neurotoxic effects of phentermine, probably by increasing phentermine brain levels. The clinical significance of these findings remains to be ascertained. Copyright 2000 Wiley-Liss, Inc.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11044894&dopt=Abstract fluoxetine




Pol J Pharmacol. 2000 May-Jun;52(3):229-35.
Effect of repeated desipramine and fluoxetine administration on post-adjuvant arthritis.

Kubera M, Cyrul W, Basta-Kaim A, Budziszewska B, Leskiewicz M, Holan V.

Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow.

The effects of desipramine and fluoxetine on the swelling of hind paws, radiologically-detectable bone destruction of hind paws, increase in spleen and popliteal lymph node weight, increase in metabolic activity of splenocytes and increase in proliferative activity of splenocytes and popliteal lymph node cells from right adjuvant injected paw in male C57BL/6 mice were studied on the 17th day after induction of post-adjuvant arthritis. Drugs were administered once-daily ip at a dose of 10 mg/kg. Fourteen days of desipramine administration, starting on the third day after injection of the adjuvant, significantly increased edema and radiologically assessed bone destruction, spleen and popliteal lymph node weight whereas fluoxetine induced an opposite effect, but it did not reduce edema in comparison with saline-treated control. Two-week desipramine administration significantly increased metabolic activity of splenocytes and proliferative activity of popliteal lymph node cells from the right adjuvant-injected paw, whereas 14 days of fluoxetine injection reduced proliferative activity of splenocytes in comparison with the saline-treated mice. Desipramine administration 30 days before and 17 days after adjuvant injection did not change these parameters in spite of reduction of proliferative activity of splenocytes. These findings indicate that: 1) fluoxetine has a suppressive effect on some of the local and systemic changes which occur in adjuvant-induced arthritis in mice, 2) two-week desipramine administration significantly increases whereas 47-day desipramine treatment does not change most of local and systemic parameters of post-adjuvant disease in C57BL/6 mice, 3) the action of fluoxetine differs from th




Pharmacol Biochem Behav. 2001 May-Jun;69(1-2):189-93.
Potentiation of kappa-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine.

Nemmani KV, Gullapalli S, Ramarao P.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Phase-X, S.A.S., 160 062 (Pb), Nagar, India.

The effect of fluoxetine, a selective 5-HT reuptake inhibitor on the analgesic and hypothermic response of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulphonate (U-50,488H) and (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzo[b] thiophene-4-acetamide (PD 117302), kappa-opioid receptor agonists, was determined in female Sprague-Dawley rats using the tail-flick method and telethermometer, respectively. Intraperitoneal injections of U-50,488H (U50) and PD 117302 (PD117) produced a dose-dependent analgesic and hypothermic response. Fluoxetine (10 mg/kg, i.p.) by itself did not produce an analgesic response. The analgesic response to U50 (10, 20, and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine injected intraperitoneally 60 min prior to the injection of kappa-opioid agonists. Similarly, the hypothermic response of U50 (20 and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine. The results indicate that selective kappa-opioid receptor agonists-induced analgesia and hypothermia is potentiated by fluoxetine, suggesting the role of extracellular 5-HT in the kappa-opioid receptor-mediated analgesia and hypothermia.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11420085&dopt=Abstract fluoxetine




Br J Clin Pharmacol. 2001 Jul;52(1):96-9.
Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects.

Liu ZQ, Cheng ZN, Huang SL, Chen XP, Ou-Yang DS, Jiang CH, Zhou HH.

Pharmacogenetics Research Institute, Hunan Medical University, Changsha, Hunan 410078, China.

AIMS: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects. METHODS: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography. RESULTS: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively. CON




J Neurosci. 2001 Aug 15;21(16):5871-84.
Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine.

Ranganathan R, Sawin ER, Trent C, Horvitz HR.

Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

We isolated two mutants defective in the uptake of exogenous serotonin (5-HT) into the neurosecretory motor neurons of Caenorhabditis elegans. These mutants were hypersensitive to exogenous 5-HT and hyper-responsive in the experience-dependent enhanced slowing response to food modulated by 5-HT. The two allelic mutations defined the gene mod-5 (modulation of locomotion defective), which encodes the only serotonin reuptake transporter (SERT) in C. elegans. The selective serotonin reuptake inhibitor fluoxetine (Prozac) potentiated the enhanced slowing response, and this potentiation required mod-5 function, establishing a 5-HT- and SERT-dependent behavioral effect of fluoxetine in C. elegans. By contrast, other responses of C. elegans to fluoxetine were independent of MOD-5 SERT and 5-HT. Further analysis of the MOD-5-independent behavioral effects of fluoxetine could lead to the identification of novel targets of fluoxetine and could facilitate the development of more specific human pharmaceuticals.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11487610&dopt=Abstract fluoxetine




Restor Neurol Neurosci. 2000;17(4):211-216.
Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats.

Jolkkonen J, Puurunen K, Rantakomi S, Sirvio J, Haapalinna A, Sivenius J.

Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.

Purpose: The present study investigated the effects of fluoxetine, a serotonin reuptake blocker, on behavioral deficits of rats subjected to transient focal cerebral ischemia. Methods: The right middle cerebral artery of rats was occluded for 120 min using the intraluminal filament method. Fluoxetine treatment (5 mg/kg, i.p.) was started 2 days after ischemia induction and treatment was continued for 10 days thereafter. Sensorimotor recovery was assessed using the limb-placing test and cognitive impairment was assessed using a water-maze test at the end of the experiment. Results: Fluoxetine treatment did not improve performance of ischemic rats in the limb-placing test. Nor was the ischemia-induced deficit in the water-maze test affected by fluoxetine. The infarct volumes in the cortex or striatum, determined after the experiment, were not different between ischemic groups. Conclusion: These results suggest that subchronic fluoxetine treatment following experimental focal cerebral ischemia is not detrimental to behavioral outcome, but it also does not enhance spontaneous sensorimotor recovery or attenuate spatial learning deficits.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11490091&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 2001 Sep;298(3):1083-91.
Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse.

Knobelman DA, Hen R, Lucki I.

Department of Pharmacology and Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6140, USA.

The regulation of extracellular levels of 5-hydroxytryptamine (serotonin) (5-HT) in the striatum and ventral hippocampus was studied using in vivo microdialysis in awake, unrestrained wild-type 5-HT(1A) and 5-HT(1B) receptor knockout mice. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine evoked a significant dose-dependent increase in extracellular 5-HT in both the striatum and hippocampus at both 2.5 mg/kg (i.p.) and 20 mg/kg (i.p.) in wild-type mice. In 5-HT(1A) receptor knockout mice, the response to 2.5 mg/kg fluoxetine was significantly augmented in the striatum but not the hippocampus, whereas the response to 20 mg/kg fluoxetine was significantly greater in both brain regions. In 5-HT(1B) receptor knockout mice, the increase of extracellular 5-HT was augmented in the hippocampus but not the striatum at both doses of fluoxetine. The response pattern to fluoxetine alone in 5-HT receptor mutant mice corresponded with the effects of fluoxetine given with either the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg i.p.) or the 5-HT(1B/1D) receptor antagonist GR 127935 (0.056 mg/kg) in wild-type mice. These results indicate common topographical regulation of 5-HT release in different brain regions by genetic mutation and pharmacological challenges. The 5-HT(1A) autoreceptor plays a larger role in regulating 5-HT release in the striatum and possibly other brain regions innervated by the dorsal raphe nucleus, whereas the role of the 5-HT(1B) receptor is relatively greater in the hippocampus and possibly other brain regions innervated by the median raphe nucleus.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11504805&dopt=Abstract fluoxetine




Eur J Nucl Med. 2000 Sep;27(9):1402-4.
Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results.

Capa Kaya G, Durak H, Yemez B, Turhal U, Ozdogan O, Sayit E, Degirmenci B, Derebek E.

Department of Nuclear Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.

Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36+/-12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq 99mTc-DTPA for 3 min, lung images in a 64x64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T 1/2) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of 99mTc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53+/-0.03 and 0.49+/-0.05 respectively, P< or =0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT