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Fluoxetine gradually increases [125I]DOI-labelled 5-HT2A/2C receptors in the hypothalamus without changing the levels of Gq- and G11-proteins.

Li Q, Muma NA, Battaglia G, Van de Kar LD.

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

The time course of fluoxetine-induced supersensitivity of hypothalamic 5-HT2A/2C receptors was examined. Daily injections of fluoxetine (7 or 14 days) significantly increased agonist ([125I]DOI)-labeled high-affinity-state 5-HT2A/2C receptors in the hypothalamus, but not frontal cortex. No change was observed in the density of [3H]ketanscrin-labeled 5-HT2A receptors in either brain region. The levels of Gq- and G11- proteins in the hypothalamus and cortex were not altered by fluoxetine. These results suggest that fluoxetine gradually increases the G-protein coupling of 5-HT2A/2C receptors without altering the levels of Gq- or G11-proteins.

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Pharmacokinetics and antidepressant activity of fluoxetine in transgenic mice with elevated serum alpha-1-acid glycoprotein levels.

Holladay JW, Dewey MJ, Yoo SD.

College of Pharmacy, Howard University, Washington, DC 20059, USA.

Fluoxetine, a novel selective serotonin reuptake inhibitor utilized in the treatment of depression, is avidly bound to serum albumin and alpha-1-acid glycoprotein (AAG). AAG is an acute phase protein, and its serum levels are elevated in a variety of pathophysiological conditions including inflammation, depression, cancer, and acquired autoimmune deficiency syndrome. Further, the pharmacokinetic disposition and pharmacological activity of several highly bound drugs have been reported to be significantly altered as a result of elevated serum AAG. We investigated the effects of elevated serum AAG levels on the pharmacokinetic disposition, antidepressant activity, and steady state profile of fluoxetine and its demethylated metabolite, norfluoxetine. This was approached utilizing a novel strain of transgenic mice that expressed genetically elevated serum AAG levels severalfold over those of control mice. Serum and brain drug concentrations were determined by HPLC after fluoxetine administration. In transgenic mice, the volume of distribution and the terminal elimination half-life of fluoxetine were significantly reduced. Further, significant reductions in brain-to-serum fluoxetine concentration ratios and antidepressant activity were observed in transgenic mice, despite having higher serum drug levels than control mice. This trend in the serum continued at steady state, and brain fluoxetine levels were significantly lower in transgenic mice. The results of this study provide valuable insights regarding the consequences of elevated serum AAG levels, often seen in several disease states, on the pharmacokinetic disposition of fluoxetine.

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Fluoxetine increases norepinephrine release in rat hypothalamus as measured by tissue levels of MHPG-SO4 and microdialysis in conscious rats.

Perry KW, Fuller RW.

Central Nervous System Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.

The selective serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) increased tissue levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat hypothalamus, indicating an increased release of norepinephrine. Microdialysis studies in conscious rats showed that fluoxetine (10 mg/kg i.p.) increased extracellular concentrations of norepinephrine as well as serotonin in the hypothalamus. In contrast, desipramine (10 mg/kg i.p.) increased extracellular concentration of norepinephrine but not serotonin in the hypothalamus. Consistent with its mechanism of being a selective serotonin uptake inhibitor, local perfusion of fluoxetine (10 microM) caused a 7-fold increase in hypothalamic extracellular serotonin and a small non-significant increase in extracellular norepinephrine. The subsequent systemic injection of fluoxetine (10 mg/kg s.c.) after local perfusion caused a 3-fold increase in extracellular norepinephrine, indicating that fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.

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Effects of the selective serotonin reuptake inhibitor fluoxetine on social behaviors in male and female prairie voles (Microtus ochrogaster).

Villalba C, Boyle PA, Caliguri EJ, De Vries GJ.

Department of Psychology, University of Massachusetts, Amherst 01003-7710, USA.

The selective serotonin reuptake inhibitor fluoxetine modifies social behavior in a number of species, including humans. Because the neural substrates for social behavior in prairie voles are sexually dimorphic, we tested whether the effects of fluoxetine on these behaviors differ by sex. Parental and pair-bonded voles were chronically treated with fluoxetine or saline and subsequently tested for parental responsiveness. Fluoxetine-treated animals displayed a longer latency to exhibit parental responsiveness than did saline-treated controls (p < 0.02), but they did not differ in other aspects of parental care. There were no sex differences in the effects of fluoxetine on parental behavior. After completion of the tests for parental behavior, the subjects were tested for aggressive behavior using the resident-intruder paradigm. Fluoxetine-treated males displayed less aggressive behavior than their saline-treated counterparts (p < 0.02). Although we did not find any effects of fluoxetine on aggressive behavior in females, no significant interaction was found between sex and treatment. Fluoxetine did not alter nonsocial behaviors. The findings suggest that serotonin influences social behavior in prairie voles.

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Routine measurement of fluoxetine and norfluoxetine by high-performance liquid chromatography with ultraviolet detection in patients under concomitant treatment with tricyclic antidepressants.

Meineke I, Schreeb K, Kress I, Gundert-Remy U.

Department of Clinical Pharmacology, University of Goettingen, Germany.

A robust and rapid high-performance liquid chromatography (HPLC) method is described for therapeutic drug monitoring of fluoxetine and norfluoxetine in the presence of six frequently-used tricyclic antidepressants and their respective metabolites. Liquid-liquid extraction into n-hexane/acetonitrile is used with reextraction into hydrochloric acid for clean-up. The chromatographic separation is carried out on a CN column. The minimum detectable amount is 3 ng injected on column. In addition to qualitative and quantitative validation data for the assay method, results from patient samples are presented. It is concluded that for patients treated with fluoxetine, therapeutic drug monitoring is valuable for optimizing the therapy.

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Issues in methodology and applications for therapeutic drug monitoring of fluoxetine and norfluoxetine enantiomers.

Zuccaro P, Pacifici R, Altieri I, Avenoso A, Pellegrini M, Spina E, Perucca E, Pichini S.

Clinical Biochemistry Department, Istituto Superiore di Sanita, Roma, Italy.

A standardization of the analytical procedures for monitoring of fluoxetine and norfluoxetine enantiomers is described. Simultaneous determination of fluoxetine and norfluoxetine enantiomers in plasma and serum was performed by high-performance liquid chromatography with a chiral stationary phase, using ultraviolet absorbance detection. The analytes were extracted from the biologic matrix by alkalinization with NaOH and solid-phase extraction. Stability studies were conducted in EDTA, lithium-heparinized plasma and in serum spiked with the analytes stored at +4 degrees C for 1 week and at -20 degrees C for 1 month. Furthermore, stability studies in NaOH and in the extraction solvents were executed. Using this methodology, EDTA plasma is the most suitable matrix for drug monitoring, even if the storage should not exceed 3 weeks at -20 degrees C. Furthermore, the biologic sample should be left in NaOH for a short time before solid-phase extraction to prevent a degradation of matrix, which would interfere with the chromatographic analysis.

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Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.

Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A.

The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.

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5HT1A receptor antagonists enhance the functional activity of fluoxetine in a mouse model of feeding.

Li DL, Simmons RM, Iyengar S.

Lilly Neuroscience, Mail Code 0510, Lilly Research Laboratories, Eli Lilly, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Fluoxetine has been reported to suppress food intake in animal models of feeding. Fluoxetine increases extracellular serotonin in the brain. 5HT1A autoreceptors regulate synaptic levels of serotonin. A combination of a 5HT1A receptor antagonist and fluoxetine has been previously reported to enhance extracellular levels of serotonin over what is obtained with fluoxetine alone. Thus, a combination of fluoxetine and a 5HT1A antagonist could enhance the ability of fluoxetine to suppress appetite. Fluoxetine was tested in a model of feeding, in which CD-1 mice were trained to drink sweetened condensed milk. Fluoxetine was found to attenuate milk drinking, in a dose-dependent manner, at doses greater than 10 mg/kg, i.p. A 10 mg/kg dose of fluoxetine, which was ineffective by itself, was then combined either with 5-hydroxytryptophan (5HTP), a serotonin precursor, or with S(-) pindolol, a 5HT1A/beta adrenergic receptor antagonist or with LY206130, a more selective 5HT1A receptor antagonist. These treatment paradigms resulted in significant attenuation of the consumption of sweetened condensed milk. Since fluoxetine has been shown to be useful in the treatment of eating disorders and to promote weight loss in obese humans, although at doses greater than those required for the treatment of depression, a combination of fluoxetine with a 5HT1A receptor antagonist could be of clinical utility in the treatment of eating disorders and obesity. Copyright 1998 Elsevier Science B.V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9507085&dopt=Abstract fluoxetine Prozac