Prozac
Chronic fluoxetine suppresses circulating estrogen and the enhanced spatial learning of estrogen-treated ovariectomized rats.

Taylor GT, Farr S, Klinga K, Weiss J.

Behavioral Neuroscience Group, University of Missouri--St. Louis, 8001 Natural Bridge Road, St. Louis, MO 63121, USA. geot umsl.edu

We are interested in developing animal models to evaluate cognitive processes as influenced by the interplay of steroidal hormones and drugs commonly used in psychotherapy. Two experiments with female rats were conducted to evaluate the interaction of estrogen with the serotonin specific reuptake inhibitor (SSRI) fluoxetine on spatial learning and memory and on the endocrine system. In experiment 1, estrogen (50 microg estradiol benzoate/kg body weight) was administered SC to young adult, ovariectomized (OVX) rats either alone or in combination with fluoxetine (2 mg/kg SC). After a month, the groups were compared with appropriate OVX and gonadally intact controls on trials to criterion in a hole board spatial memory task using massed training trials. Experiment 2 was a dose-response study of the influence of fluoxetine (0.5-5 mg/kg) on circulating estrogen in OVX, estrogen treated females. Results were that the OVX females administered estrogen only reached the learning criterion significantly faster than the other groups. All other groups, including the estrogen + fluoxetine animals, performed no better than the controls. Combining fluoxetine with estrogen also lowered circulating estrogen titers, with the least estrogen reductions being in the group receiving the highest dosage of fluoxetine. No differences among groups were found on measures of activity in an open field or for anxiety in a plus maze. Conclusions were that administration of estrogen improved spatial learning and memory in OVX rats, whereas concurrent fluoxetine exposure suppressed the levels of estrogen in circulation and eliminated the gains in spatial performance obtained from chronic estrogen exposure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15288703&dopt=Abstract fluoxetine Prozac



Prozac
Subchronic administration of fluoxetine impairs estrous behavior in intact female rats.

Matuszczyk JV, Larsson K, Eriksson E.

Department of Psychology, University of Goteborg, Sweden.

Treatment with serotonin reuptake inhibitors (SRIs) has been shown to cause reduced libido and anorgasmia in women. A large body of evidence suggests that serotonin may influence sexual behavior in estradiol + progesterone primed, gonadectomized female rats; however, the influence of selective SRIs on the estrous behavior of intact female rats has not been described previously. In the present study, the effect of 1 to 3 weeks of fluoxetine administration (10 mg/kg daily) on vaginal and behavioral estrus in intact female rats was studied; in addition, the effect of fluoxetine (same dose, 1-8 weeks) on copulatory behavior and on sexual motivation in hormone-primed gonadectomized rats was investigated. Subchronic administration of fluoxetine did not influence cyclicity as judged by the examination of vaginal smears but significantly reduced the percentage of rats displaying receptive behavior in the estrous phase. In addition, fluoxetine significantly reduced receptive behavior, including lordosis, in ovariectomized female rats primed with estradiol (6.25 micrograms/rat; -48 hr) plus progesterone (1.0 mg/rat, -4 hr); in contrast, sexual motivation--as reflected by the amount of time these rats elected to spend in the vicinity of a male rather than in the vicinity of a female or elsewhere--was little affected by the treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9803425&dopt=Abstract fluoxetine Prozac



Prozac
Evaluation of the binding of the radiolabeled antidepressant drug, 18F-fluoxetine in the rodent brain: an in vitro and in vivo study.

Mukherjee J, Das MK, Yang ZY, Lew R.

Department of Radiology, Franklin McLean Institute, University of Chicago, IL 60637, USA. jogeshwar_mukherjee ketthealth.com

We have developed 18F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of 18F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of 18F-fluoxetine was not obtained. Even when fluoxetine (10 microM) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of 18F-fluoxetine. Ex vivo autoradiographic experiments with 18F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of 18F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of 18F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with 18F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of 18F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9804041&dopt=Abstract fluoxetine Prozac



Prozac
Effect of fluoxetine on extracellular 5-hydroxytryptamine in rat brain. Role of 5-HT autoreceptors.

Hervas I, Artigas F.

Department of Neurochemistry, Instituto de Investigaciones Biomedicas de Barcelona, CSIC (IDIBAPS), Spain.

Using microdialysis, we examined the effects of the antidepressant drug fluoxetine on 5-hydroxytryptamine (5-HT) output in rat brain. Fluoxetine (1, 3 and 10 mg/kg i.p.) dose dependently increased 5-HT output in the dorsal and median raphe nuclei and four forebrain areas. Maximal elevations were noted in the raphe nuclei. At 1 and 3 mg/kg, fluoxetine elicited minor or no increases of 5-HT output in the forebrain. When citalopram was present in the perfusion fluid, fluoxetine (10 mg/kg) reduced 5-HT output, an effect reversed by the administration of the selective 5-HT1A receptor antagonist inverted question markN-[2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl]-N-(2-pyridyl) cyclohexane carboxamide.3HCl inverted question mark (WAY 100635). This reduction was more marked in the frontal cortex than in the dorsal hippocampus. Consistent with this, WAY 100635 potentiated the effect of 3 and 10 mg/kg fluoxetine more in the frontal cortex than in the dorsal hippocampus. The administration of a combination of WAY 100635 (0.3 mg/kg s.c.) and the 5-HT1B/1D receptor antagonist inverted question markN-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl),[1,1-biphenyl]-4-carboxiamide inverted question mark (GR 127935; 5 mg/kg s.c.) potentiated the effect of 3 mg/kg fluoxetine to an extent similar to that of WAY 100635 alone in both areas. These results suggest that somatodendritic 5-HT1A receptors offset the effect of fluoxetine in the frontal cortex but not (or to a lesser extent) in the dorsal hippocampus. GR 127935 may have a partial antagonistic action at terminal 5-HT autoreceptors in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9809863&dopt=Abstract fluoxetine Prozac



Prozac
Sensitive, high-throughput gas chromatographic-mass spectrometric assay for fluoxetine and norfluoxetine in human plasma and its application to pharmacokinetic studies.

Addison RS, Franklin ME, Hooper WD.

Centre for Studies in Drug Disposition, Department of Medicine, The University of Queensland, Royal Brisbane Hospital, Australia.

A sensitive, robust gas chromatographic-mass spectrometric assay suitable for use in pharmacokinetic or bioequivalence studies is presented for the selective serotonin reuptake inhibitor, fluoxetine, and its major metabolite, norfluoxetine (N-desmethylfluoxetine). This method employs solid-phase extraction followed by acetylation with trifluoroacetic anhydride and analysis of the derivatives using selected ion monitoring. The lower limit of quantification was 1.0 ng/ml, and the assay was linear for both analytes from 1 to 100 ng/ml. Mean recoveries following solid-phase extraction at concentrations of 5.0, 20 and 100 ng/ml were 91% (fluoxetine) and 87% (norfluoxetine). Assay precision (as mean RSD) and accuracy (as mean relative error) for both analytes were tested at the same three nominal concentrations and were found to be within 10% in all cases. Analysis of fluoxetine concentrations in plasma samples from 18 volunteers following administration of a single 40 mg dose of fluoxetine provided the following pharmacokinetic data (mean+/-SD): Cmax, 32.73+/-9.21 ng/ml; AUC0-infinity, 1627+/-1372 ng/ml h; Tmax, 3.08 h (median); ke, 0.022+/-0.007 h(-1); elimination half-life, 37.69+/-21.70 h.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9824228&dopt=Abstract fluoxetine Prozac



Prozac
Excitatory amino acids and serotonin uptake blockers reveal two physiologically distinct serotonin systems in the retina of the skate, Raja erinacea.

Schuette E, Chappell RL.

Hunter College and the Graduate School of the City University of New York, Department of Biological Sciences, NY 10021, USA.

The retina of the skate (Raja erinacea) contains at least 2 types of cell (amacrines and bipolars) that can be visualized with an antiserum against serotonin. We have employed serotonin immunocytochemistry in combination with pharmacological manipulation of retinal tissue to analyze physiological properties of serotonergic amacrine cells and serotonin-accumulating bipolar cells. Excitatory amino acids (NMDA, aspartate) had no detectable effects on serotonin-immunoreactivity in bipolar cells but decreased staining in amacrine cells. High K+ Ringer increased staining in bipolar cell somata, however, it depleted the inner plexiform layer of the retina of serotonin. Zimelidine, a serotonin uptake inhibitor, completely blocked serotonin accumulation by bipolar cells but had no effect on amacrine cells, whereas incubation of the retinas in fluoxetine (Prozac), a different inhibitor of serotonin uptake, did not block serotonin accumulation into bipolar cells which was actually enhanced in some cases. We conclude that amacrine and bipolar cells of the skate retina employ two different serotonin uptake carrier systems, thus generating two distinct pharmacological components that are capable of interacting with each other as they compete for extracellular serotonin. Similar mechanisms may exist in the vertebrate CNS and further examination of the interaction of these systems could provide important insights into the action and possible side effects of serotonin-related drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9845022&dopt=Abstract fluoxetine Prozac



Prozac
Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins.

Raap DK, Evans S, Garcia F, Li Q, Muma NA, Wolf WA, Battaglia G, Van De Kar LD.

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

The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9862759&dopt=Abstract fluoxetine Prozac



Prozac
Determination of fluoxetine and norfluoxetine in human plasma by high-pressure liquid chromatography with fluorescence detection.

Raggi MA, Mandrioli R, Casamenti G, Bugamelli F, Volterra V.

Dipartimento di Scienze Farmaceutiche, Universita di Bologna, Italy. antox kaiser.alma.unibo.it

Fluoxetine is an atypical antidepressant drug, which selectively inhibits the neuronal reuptake of serotonin, and is widely used in the treatment of depressive disorders. The aim of this research is the development of an HPLC method with fluorescence detection for the monitoring of fluoxetine plasma levels. The determination requires no more than 250 microl of plasma, which undergo solid phase extraction (SPE), then are injected in the HPLC. For the analytical separation a reversed phase C8 column (150 x 4.6 mm I.D.) was used, while the mobile phase was a mixture of acetonitrile and water containing perchloric acid and tetramethylammonium perchlorate (flow rate: 1 ml min(-1)). The very low levels of analytes in plasma required the employment of a fluorescence detector (lambda(exc) = 230 nm, lambda(em)=290 nm), which also granted a good selectivity. Fluoxetine is revealed as a single peak at a retention time of 9.7 min, while norfluoxetine, the main metabolite of fluoxetine, is revealed at a retention time of 8.1 min. Linearity was obtained over the concentration range 8-200 ng ml(-1) for both substances. The method seems suitable, in accuracy and precision, for the determination of fluoxetine plasma levels of patients; furthermore, it is rapid and sensitive.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9863958&dopt=Abstract fluoxetine Prozac