Prog Neuropsychopharmacol Biol Psychiatry. 1997 Jan;21(1):169-81.
Dopaminergic and serotonergic properties of fluoxetine.

Simon B, Appel JB.

Department of Psychology, University of South Carolina, Columbia, USA.

1. Rats were trained to discriminate i.p. injections of a 5-HT agonist, LSD (0.08 mg/kg, n = 12) or a DA agonist, cocaine (10 mg/kg; n = 16) in a two lever, drug discrimination situation. 2. Animals were tested with fluoxetine (0.625-10 mg/kg) alone and in combination with low doses of the training drugs. 3. Fluoxetine did not substitute for either LSD or cocaine at any dose tested. A relatively low dose of fluoxetine (2.5 mg/kg) potentiated the discriminability of cocaine (2.5 mg/kg) from saline. A higher dose of fluoxetine (5.0 mg/kg) significantly enhanced the effects of a low dose of LSD (0.02 mg/kg), but only to 41.7% responses on the LSD-appropriate lever. 4. The data suggest that fluoxetine alters the discriminative stimulus properties of cocaine to a greater extent than those of LSD. 5. The ability of fluoxetine to potentiate the cocaine cue (but not to substitute for cocaine) suggests that both of those drugs affect DA systems, but do so through different mechanisms. For example, fluoxetine may not inhibit DA reuptake (to the same extent as cocaine), but may have other dopaminergic actions such as increasing DA receptor density.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9075265&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1997 Apr;281(1):115-22.
Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells.

Beck SG, Birnstiel S, Choi KC, Pouliot WA.

Department of Pharmacology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, USA.

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve




Eur J Pharmacol. 1997 Mar 26;323(1):69-73.
Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.

Smith JE, Lakoski JM.

Department of Pharmacology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey 17033, USA.

The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing. When duloxetine was co-applied with 5-HT, the recovery response (RT50 values) of hippocampal pyramidal neurons to 5-HT application was not altered. In contrast, co-application of fluoxetine with 5-HT at the same iontophoretic currents significantly increased (59%) the RT50 values produced by 5-HT application alone. This physiological and pharmacological study contributes to understanding the cellular mechanisms of these agents which may be useful in the treatment of depression.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9105878&dopt=Abstract fluoxetine




J Toxicol Clin Toxicol. 1997;35(3):269-76.
In vitro adsorption study of fluoxetine onto activated charcoal at gastric and intestinal pH using high performance liquid chromatography with fluorescence detector.

Tsitoura A, Atta-Politou J, Koupparis MA.

University of Athens, Greece.

BACKGROUND: This in vitro investigation was performed to study the adsorption characteristics of fluoxetine to activated charcoal and its commercial formulation Carbomix powder in simulated gastric (pH = 1.2) and intestinal (pH = 7.2) fluid environments. METHODS: Solutions containing fluoxetine and charcoal were incubated at 37 degrees C for one hour. Reversed phase high performance liquid chromatography was used for the determination of free fluoxetine concentrations (range 0.2-8 micrograms/mL) in the diluted filtrate. RESULTS: The maximum adsorption capacities at pH 1.2 for activated charcoal and Carbomix were 223 and 333 mg/g, respectively; at pH 7.2 they were 301 and 453 mg/g, respectively. The affinity constant values at pH 1.2 of activated charcoal and Carbomix were 441 and 122 L/g, respectively, while at pH 7.2 they were 482 and 589 L/g, respectively, indicating a strong binding of fluoxetine onto charcoals. CONCLUSIONS: Relative to the toxic and lethal doses in cases of fluoxetine intoxications, both types of charcoals tested were found effective for adsorption at gastric and intestinal pH. Adsorbed fluoxetine was significantly increased at intestinal pH, consistent with predominant adsorption of the undissociated form of the drug. We conclude that activated charcoal and Carbomix have adsorptive properties appropriate to medical treatment in cases of fluoxetine overdose.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140321&dopt=Abstract fluoxetine




Neuropsychopharmacology. 1997 Jun;16(6):419-25.
An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress.

Page ME, Abercrombie ED.

Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102, USA.

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9165497&dopt=Abstract fluoxetine




Obstet Gynecol. 1997 May;89(5 Pt 1):713-8.
Effects of first-trimester fluoxetine exposure on the newborn.

Goldstein DJ, Corbin LA, Sundell KL.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

OBJECTIVE: To determine whether first-trimester exposure to fluoxetine, a selective serotonin reuptake inhibitor commonly used to treat depression and obsessive-compulsive disorders, is associated with increased frequency of fetal malformations. METHODS: We evaluated outcomes of all pregnancies identified prospectively with confirmed first-trimester fluoxetine exposure contained in the Eli Lilly and Company worldwide fluoxetine pregnancy registry. These outcomes were compared with historic reports of newborn surveys. RESULTS: Outcomes were available for 796 pregnancies, 37 from fluoxetine clinical trials and 759 from spontaneous reports. Spontaneous abortions were reported in 110 of the 796 (13.8%) pregnancies. Of the remaining 686, malformations, deformations, and disruptions, including those identified after the perinatal period, were reported in 34 (5.0%). No consistent or recurring pattern of abnormalities was observed. CONCLUSION: Based on comparison with historic reports of newborn surveys, it is unlikely that maternal fluoxetine use during the first trimester of pregnancy results in increased risk of fetal malformations.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9166307&dopt=Abstract fluoxetine




J Pharm Biomed Anal. 1997 Mar;15(6):729-38.
Single pump column switching technique employing a flow gradient and wavelength programmed fluorescence for simultaneous monitoring of serotonin, fluoxetine and norfluoxetine in rat brain microdialysate.

Ramaiya A, March C, Karnes HT.

Department of Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0533, USA.

A single pump column switching technique with multidimensional chromatography, flow gradient and wavelength programmed fluorescence detection was developed for simultaneous quantitation of serotonin, fluoxetine and norfluoxetine in rat brain microdialysate. The column switching was configured such that position I of the switching valve employed column I (50 mm length) and column II (250 mm length) in series. This configuration resulted in optimal resolution of serotonin from interfering neurochemicals from rat brain. After elution of serotonin at 13.2 min the valve was switched to position II in which the flow of the mobile phase was directed through column I only. Flow gradient programming was then used to ramp the flow rate from 0.1 to 0.4 ml min-1 which resulted in optimal elution of fluoxetine and norfluoxetine. Strategic optimization of the single mobile phase enabled use of a single pump and detector making the analytical system simple and cost effective. Wavelength programmed fluorescence enabled sensitive detection of the analytes despite the difference in their fluorescence spectrum. The limit of detection for serotonin, norfluoxetine and fluoxetine were 10, 612 and 523 fmol, respectively. Rat brain microdialysate samples demonstrated selectivity for serotonin, fluoxetine and norfluoxetine. The method demonstrates application to the study of site specific neuropharmacokinetics and neuropharmacodynamics of fluoxetine in vivo.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9172098&dopt=Abstract fluoxetine




J Chromatogr B Biomed Sci Appl. 1997 May 9;692(2):337-43.
Direct analysis of fluoxetine and norfluoxetine in plasma by gas chromatography with nitrogen-phosphorus detection.

Fontanille P, Jourdil N, Villier C, Bessard G.

Laboratoire de Pharmacologie, Centre Hospitalier Universitaire de Grenoble, France.

A quantitative method for the simultaneous GC resolution and detection of fluoxetine and his metabolite norfluoxetine in human plasma was developed. The procedure required 1.0 ml of plasma, extraction with a mixed organic solvent and injection into a capillary gas chromatograph with an OV-1 fused-silica column coupled to a nitrogen-phosphorus detector. The calibration curves were linear over the range 5-3000 ng/ml. The detection limits were 0.3 and 2 ng/ml for fluoxetine and norfluoxetine, respectively. The assay is suitable for routine analysis.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9188822&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1997 Jun;281(3):1487-98.
Selective serotonin reuptake inhibitors dissociate fenfluramine's anorectic and neurotoxic effects: importance of dose, species and drug.

McCann UD, Yuan J, Hatzidimitriou G, Ricaurte GA.

Biological Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892-1272, USA.

Fenfluramine, a clinically prescribed appetite suppressant, has been found to damage brain serotonin (5-HT) neurons in every animal species tested to date. Recent findings indicate that fluoxetine, a selective 5-HT reuptake inhibitor (SSRI), can prevent fenfluramine-induced 5-HT neurotoxicity without blocking fenfluramine-induced appetite suppression. The purpose of our studies was several-fold: 1) To determine whether the ability for fluoxetine to dissociate fenfluramine-induced anorexia and neurotoxicity is dose-related; 2) to ascertain whether other SSRIs also prevent fenfluramine-induced neurotoxicity without altering its anorectic effect; 3) to determine whether similar fluoxetine/fenfluramine interactions are seen in another animal species (i.e., mice) and 4) to determine whether decreases in food intake seen after the fluoxetine/fenfluramine combination can be attributed to nonspecific behavioral suppression. Results from our studies indicate that fluoxetine's effects are, indeed, dose-related, because higher doses of fluoxetine are required to protect against the 5-HT neurotoxic effects of higher doses of fenfluramine. Further, our results indicate that fluoxetine's effects generalize to all other SSRIs tested (citalopram, paroxetine and sertraline), as well as to other species (mice). Finally, our results demonstrate that anorexia in animals receiving the fenfluramine/fluoxetine combination is not secondary to nonspecific behavioral suppression, because water intake is increased although food intake is decreased in the same animals. Together, these data suggest that the anorectic and 5-HT neurotoxic effects of fenfluramine may involve different mechanisms, a