psych.toronto.edu

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5-1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10090650&dopt=Abstract fluoxetine




Brain Res. 1999 Apr 3;824(1):28-35.
Fluoxetine-induced plasticity in the rodent visual system.

Bastos EF, Marcelino JL, Amaral AR, Serfaty CA.

Departamento de Neurobiologia, Universidade Federal Fluminense, Caixa Postal 100180, Niteroi, CEP 24001-970, RJ, Brazil.

We studied the effect of fluoxetine, a selective serotonin reuptake inhibitor, in the development and lesion-induced plasticity of retinotectal axons in pigmented rats. Neonatal rats received a daily injection of either fluoxetine or vehicle from postnatal day 1 (PND 1) to PND 10 or from PND 14 to PND 28 (fluoxetine, 7.5 and 10.0 mg/kg, respectively). In the latter group, some animals received a single lesion at the temporal periphery of the left retina at PND 21. Unoperated animals were use as the control. At the end of the treatment, the animals received an intraocular injection of horseradish peroxidase (HRP) in the right (intact) eye to trace the uncrossed retinotectal pathway. Chronic fluoxetine treatment, induced, in unoperated rats, an expansion of the retinal terminal fields along the rostro-caudal axis of the tectum both in the PND 10 and PND 28 groups. Following a retinal lesion in the left eye at PND 21, the vehicle-treated group showed a small reorganization of the intact uncrossed projection. In this group only a few terminals were labeled invading the denervated tectal surface one-week after the lesion. Fluoxetine-treated animals on the other hand, showed a great amplification of plasticity with a conspicuous sprouting of the uncrossed retinal axons into denervated areas. The data suggest that fluoxetine induces extensive axonal rearrangements in neonatal and juvenile central nervous system and amplifies neuroplasticity following retinal lesions late in development. Copyright 1999 Published by Elsevier Science B.V.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10095039&dopt=Abstract fluoxetine




Br J Pharmacol. 1998 Sep;125(2):301-8.
A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents.

Heal DJ, Cheetham SC, Prow MR, Martin KF, Buckett WR.

Knoll Pharmaceuticals Research & Development, Nottingham.

1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine. 2. In vitro sibutramine weakly inhibited [3H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]-5-HT from brain slices at < or = 10(-5)M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [3H]-5-HT release. 3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses < 10 mg kg(-1). In contrast, (+)-amphetamine ( > or = 3 mg kg(-1)) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (> or =1 mg kg(-1)) decreased 5-HTP in both regions. 4. Sibutramine (10 mg kg(-1) i.p.) and fluoxetine (10 mg kg(-1) i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg(-1) i.p.) and (+)-amphetamine (4 mg kg(-1) i.p.) induced rapid, short-lasting increases in extracellular 5-HT. 5. Only (+)-fenfluramine (10 mg kg(-1)) altered 5-HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity. 6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by incr

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.

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

farmaco.odon.uba.ar

The aim of this work was to study whether long-term treatment with fluoxetine could induce peripheral effects by modifying vas deferens contractile activity. For this purpose the contractile response to NE, and 5-HT of vas deferens isolated from male Wistar rats that received fluoxetine 10 mg/kg/day i.p., during 21 days, was studied using the isolated organ bath technique. Results show that vas deferens of treated rats presented spontaneous activity, an effect that was abolished by prazosin and isoproterenol and that was not affected by nitroprusside or indomethacin. In addition, fluoxetine did not modify the response to calcium suggesting that spontaneous activity was not a consequence of an abnormal calcium movement. Fluoxetine induced a significant increase in the response of vas deferens to 5-HT and to low NE concentrations while NE maximal effect was unaffected. Fluoxetine treatment did not modify the binding parameters of [3H]-prazosin to vas deferens. It is concluded that long-term treatment with fluoxetine modifies vas deferens contractile activity. This effect could be the result of an alteration of adrenergic neurotransmission and could account for some of the untoward effects observed during clinical course with fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10096441&dopt=Abstract fluoxetine




Eur J Pharmacol. 1998 Sep 25;358(1):9-18.
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.

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




J Chromatogr B Biomed Sci Appl. 1998 Sep 25;716(1-2):153-60.
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.

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




J Pharmacol Exp Ther. 1999 Jan;288(1):98-106.
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 red

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.

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