Prozac
Fluoxetine increases extracellular levels of 3-methoxy-4-hydroxyphenylglycol in cultured COLO320 DM cells.

Yue CT, Liu YL.

Department of Pathology, National Cheng Kung University, Taiwan, R.O.C.

Fluoxetine (Prozac) is a serotonin reuptake inhibitor. It increases extracellular levels of serotonin and is used in relieving the depressive symptoms of cancer patients. It has been reported that the drug may enhance the growth of certain cancer cells. This study investigates whether fluoxetine enhances the growth of a human colon cancer cell line (COLO320 DM) and if it affects the extracellular levels of serotonin or its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) and other monoamines and metabolites at two cell densities. The extracellular levels of serotonin, 5-HIAA and other monoamines and metabolites were measured simultaneously by high performance liquid chromatography from cell-culture media after incubation of cells both with and without fluoxetine for 3 days. The viability of COLO320 DM cells was evaluated using 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). At low cell densities (1.25x10(5) cells ml(-1)), fluoxetine at 1-10 muM significantly increased the extracellular levels of serotonin (p < 0.005), 5-HIAA (p < 0.005), and 3-methoxy-4-hydroxyphenylglycol (MHPG; p < 0.001) as compared to the controls. Fluoxetine at 10-100 muM significantly inhibited the growth of COLO320 DM (p < 0.005). At high cell densities (2x10(6) cells ml(-1)), fluoxetine at 1-10 muM significantly increased the extracellular levels of MHPG (p < 0.01), and at 10 muM it significantly increased the extracellular levels of 5-HIAA (p < 0.05). Fluoxetine at 100 muM significantly inhibited the growth of the cells (p < 0.0001). These results suggest that fluoxetine at 1 muM of effective concentration may increase the extracellular levels MHPG, in addition to serotonin and 5-HIAA levels, yet not inhibit the growth of COLO320 DM. Copyright (c) 2004 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15565631&dopt=Abstract fluoxetine Prozac



Prozac
Effects of fluoxetine on convulsions and on brain serotonin as detected by microdialysis in genetically epilepsy-prone rats.

Dailey JW, Yan QS, Mishra PK, Burger RL, Jobe PC.

Department of Basic Sciences, University of Illinois College of Medicine, Peoria.

Fluoxetine, an antidepressant and inhibitor of serotonin reuptake, was evaluated as an anticonvulsant in genetically epilepsy-prone rats (GEPRs) because seizure predisposition in GEPRs is partially dependent on deficits in brain serotonin. Fluoxetine produced dose-dependent reductions in sound-induced convulsion intensity in both moderate seizure GEPRs and severe seizure GEPRs with the peak anticonvulsant effect occurring 4 hr after i.p. administration. A subchronic study in severe seizure GEPRs demonstrated that the ED50 after 28 days of dosing (8.2 mg/kg) was lower than the acute ED50 (15.9 mg/kg) so that there was no apparent development of tolerance. The lower ED50 after subchronic administration apparently resulted from accumulation of fluoxetine and its metabolite norfluoxetine in brain. Brain microdialysis studies showed that acute fluoxetine administration resulted in a significant increase in extracellular serotonin concentration in the thalamus. The increase in serotonin concentration in the dialysate corresponded temporally with the anticonvulsant effect produced by fluoxetine. Intrathalamic administration of fluoxetine via the dialysis probe caused an increase in serotonin concentration in the dialysate, suggesting that the effect of fluoxetine was on nerve terminals. Fluoxetine could be dialyzed from thalamus after its i.p. administration. Fluoxetine concentration in the thalamic dialysate was similar to the concentration found in plasma. We conclude that fluoxetine is an effective anticonvulsant in GEPRs and that the microdialysis results strongly suggest a relationship between the effects of fluoxetine on serotonergic neurons and the anticonvulsant effect produced by this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1738103&dopt=Abstract fluoxetine Prozac



Prozac
Acute uptake inhibition increases extracellular serotonin in the rat forebrain.

Rutter JJ, Auerbach SB.

Department of Biological Sciences, Rutgers University, Piscataway, New Jersey.

The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7685386&dopt=Abstract fluoxetine Prozac



Prozac
Changes in extracellular PVN monoamines and macronutrient intake after idazoxan or fluoxetine injection.

Paez X, Leibowitz SF.

Universidad de los Andes, Merida, Venezuela.

Norepinephrine (NE) and serotonin (5-HT) in the paraventricular nucleus (PVN) have opposite effects on feeding, with NE stimulating carbohydrate intake through alpha 2 noradrenergic receptors and 5-HT inhibiting carbohydrate intake. This study examined the action of drugs that affect brain monoaminergic systems, in terms of their impact on nutrient intake and on PVN monoamines measured using microdialysis. The drugs studied were idazoxan, a blocker of alpha 2 receptors, or fluoxetine, a 5-HT reuptake blocker. In rats maintained on pure macronutrient diets, idazoxan (1 mg/kg) and fluoxetine (10 mg/kg), 120 min after injection both reduced total food intake, and specifically carbohydrate intake. In dialysis experiments, successive 20-min dialysate samples were taken, three samples before and seven samples after intraperitoneal injection of idazoxan (5 and 20 mg/kg), fluoxetine (10 mg/kg), or vehicle. Idazoxan increased NE, homovanillic acid, and dihydroxyphenylacetic acid in the PVN. Fluoxetine induced a significant increment of 5-HT in PVN, while producing a smaller increase in NE, dopamine, and homovanillic acid. These results support the conclusion that the impact of these drugs on macronutrient intake may be a consequence of their action on endogenous monoamine systems in the PVN. Thus, in this nucleus, the blockade of alpha 2-noradrenergic receptors, like stimulation of 5-HT receptors, attenuates normal ingestion of carbohydrate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7906040&dopt=Abstract fluoxetine Prozac



Prozac
Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice.

Cesana R, Ceci A, Ciprandi C, Borsini F.

Boehringer Ingelheim Italia S.p.A., Department of Pharmacology, Milano, Italy.

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8099969&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine induces vasopressin and oxytocin abnormalities in food-restricted rats given voluntary exercise: relationship to anorexia nervosa.

Aravich PF, Rieg TS, Ahmed I, Lauterio TJ.

Department of Anatomy and Neurobiology, Eastern Virginia Medical School, Norfolk 23501.

Anorexia nervosa is associated with vasopressin, oxytocin and serotonin abnormalities. Because of the relationship between exercise and anorexia nervosa, we explored the weight-loss syndrome produced by wheel running in food-deprived rats. Its effects on regional vasopressin and oxytocin concentrations were determined under basal conditions and following systemic fluoxetine. Weight-matched, exercised and unexercised rats served as controls. Fluoxetine caused abnormalities in suprachiasmatic vasopressin and dynorphin A content and in thymus oxytocin content that did not occur in weight-matched or exercised controls. No syndrome-specific anomalies occurred in the hypothalamo-neurohypophysial system or dorsal vagal complex (DVC). However, weight reduction and fluoxetine increased circulating vasopressin; moderate exercise caused fluoxetine-induced elevations in posterior pituitary vasopressin and oxytocin; and, unlike the other groups, fluoxetine increased DVC oxytocin in freely fed unexercised rats. It was concluded that syndrome-specific vasopressin and oxytocin abnormalities occur that are not secondary to weight loss or moderate exercise; that weight loss or fluoxetine increases circulating vasopressin; that moderate exercise alters neurohypophysial vasopressin and oxytocin content; and that weight loss or exercise inhibits a fluoxetine-stimulated increase in DVC oxytocin. Finally, it was argued that the fluoxetine abnormalities indicate possible serotonin dysfunction in the syndrome.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8101130&dopt=Abstract fluoxetine Prozac



Prozac
Antidepressants attenuate both the enhanced ethanol intake and ethanol-induced anxiolytic effects in diazepam withdrawn rats.

Martijena ID, Bustos SG, Bertotto ME, Molina VA.

Departamento de Farmacologia, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5016 Cordoba, Argentina. imartije fcq.unc.edu.ar

We have recently shown that the abrupt discontinuation of chronic diazepam (DZM) administration facilitated ethanol consumption and enhanced the anxiolytic properties of ethanol. Tricyclic antidepressants such as desipramine and the selective serotonin reuptake inhibitor fluoxetine have been shown to reduce alcohol intake in rodent models of alcoholism and in alcoholics who are depressed. In the present study, we tested whether desipramine (1.25; 2.5 and 5 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) treatment affect both ethanol intake in a free-choice test and the anxiolytic effect induced by ethanol in DZM withdrawn rats. Adult male Wistar rats were submitted to a chronic DZM treatment (2 mg/kg per day) or vehicle (VEH) for 21 days. Twenty-four hours after the last DZM injection, rats were subjected to a free-choice paradigm between water and increasing ethanol concentrations with or without concurrent desipramine or fluoxetine administration (ethanol concentration (v/v) was increased every 4 days as follows: 2, 4, 6, 8 and 10% for the final 8 days). Chronic treatment with desipramine (24 days, twice a day, 2.5 and 5 mg/kg, i.p.) and fluoxetine (24 days, once a day; 5 mg/kg, i.p.) significantly reduced the amount of ethanol intake in DZM withdrawn rats. Furthermore, subchronic treatments with desipramine (4 days, twice a day, 2.5 and 5 mg/kg) and fluoxetine (4 days, once a day, 5 mg/kg, i.p.) blocked the anxiolytic-like behavior in the elevated plus maze induced by ethanol (1 g/kg; i.p.) in DZM withdrawn rats at day 5 of withdrawal. The present findings suggest that desipramine and fluoxetine could be effective pharmacological tools to prevent the subsequent development of ethanol dependence in rats previously exposed to DZM withdrawal.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15572281&dopt=Abstract fluoxetine Prozac



Prozac
[Plasmatic concentrations of fluoxetine, pharmacokinetics, therapeutic response and side effects]

[Article in Spanish]

Perez Sola V, Perez Blanco J, Alvarez E, Queralto JM.

Servicio de psiquiatria, Hospital de la Santa Creu y Sant Pau, Universidad de Bellaterra, Barcelona.

The kinetics of fluoxetine and possible relations between the drug's plasmatic concentration and therapeutic response and side effects were evaluated in a sample of 66 depressive patients, 26 men and 40 women, average age 46.6 years (SD = 14.1), diagnosed according to DSM-III criteria and evaluated using the Hamilton scale for depression (17-item HRSD). We found no difference between plasmatic concentration of fluoxetine in weeks 3 and 6 of treatment, nor in the sum of drug plus active principle in weeks 3 and 6. There was no significant linear correlation between plasmatic concentrations of fluoxetine, norfluoxetine, or the sum of both in weeks 3 and 6 and score on the Hamilton scale in week 6. By means of serial Chi-score calculation we found a "minimum plasmatic concentration" of about 30 ng/ml below which there was less therapeutic response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8213289&dopt=Abstract fluoxetine Prozac