J Neural Transm. 1997;104(8-9):953-66.
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.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9451727&dopt=Abstract fluoxetine




Horm Behav. 1997 Dec;32(3):184-91.
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.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9454669&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1997 Jan;280(1):138-45.
Effect of prenatal fluoxetine (Prozac) exposure on brain serotonin neurons in prepubescent and adult male rat offspring.

Cabrera-Vera TM, Garcia F, Pinto W, Battaglia G.

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

The present study examines the consequences of prenatal fluoxetine exposure on brain serotonin [5-hydroxytryptamine (5-HT)] neurons in male offspring. Pregnant rats were administered either saline or fluoxetine (10 mg/kg s.c.) daily from gestational day 13 through gestational day 20. The biochemical status of brain 5-HT neurons was assessed in prepubescent and adult offspring by measuring 1) the 5-HT and 5-hydroxyindoleacetic acid content, 2) the density of [3H]paroxetine-labeled 5-HT uptake sites and 3) the ability of the 5-HT-releasing drug p-chloroamphetamine to reduce 5-HT content. Biochemical parameters were assessed in the frontal cortex, hypothalamus, hippocampus, striatum and midbrain. Comparative effects on dopamine and norepinephrine content in selected regions were also determined. Prenatal exposure to fluoxetine significantly reduced (-28%) 5-HT content in the frontal cortex of prepubescent but not adult male offspring. In contrast, in adult progeny prenatal fluoxetine exposure produced a significant decrease only in midbrain 5-HT content (-28%). In addition, p-chloroamphetamine markedly reduced 5-HT content in all brain regions examined, but the ability of p-chloroamphetamine to reduce 5-HT content was significantly attenuated only in the midbrain of adult progeny prenatally exposed to fluoxetine. No significant differences were observed between control and fluoxetine-exposed progeny with respect to brain 5-hydroxyindoleacetic acid content, the 5-hydroxyindoleacetic acid/5-HT ratio or the density of 5-HT uptake sites, regardless of the brain region examined or the age of the offspring. These data provide additional evidence that prena




Ther Drug Monit. 1998 Feb;20(1):20-4.
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.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9485549&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1998 Mar;59(3):595-611.
Involvement of serotonin in the modulation of cocaine-induced locomotor activity in the rat.

Herges S, Taylor DA.

Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Australia.

The influence of serotonin (5-HT) antagonists and a selective serotonin reuptake inhibitor (SSRI) on cocaine-induced locomotor activity, rears, and head bobs was investigated in female Glaxo Wistar rats. The SSRI, fluoxetine (10 mg/kg), and the nonselective 5-HT agent, methysergide, at the dose range of 5 and 15 mg/kg enhanced the behaviors produced by cocaine (15 mg/kg) to a similar extent. Moreover, the potentiation of cocaine-induced locomotor activity, rears, and head bobs was even greater after the combined administration of methysergide ( 15 mg/kg) and fluoxetine (10 mg/kg). In order to investigate a possible involvement of 5-HT1A receptors in the observed potentiation by methysergide and fluoxetine, the potent and selective 5-HT1A antagonist, WAY 100635, was used. WAY 100635 (0.1 and 1.5 mg/kg) markedly reduced the behaviors induced by cocaine preceded by fluoxetine (10 mg/kg) and methysergide (5 and 15 mg/kg) pretreatment, respectively, suggesting an involvement of 5-HT1A receptors in the action of fluoxetine and methysergide on cocaine-induced behaviors. An attenuation of the fluoxetine-enhanced cocaine-induced behaviors was also observed after pretreatment with the 5-HT2A antagonist ketanserin (0.1 and 1.0 mg/kg). Coadministration of ketanserin (1.0 mg/kg) and WAY 100635 (1.5 mg/kg) resulted in the greatest blockade of the fluoxetine-enhanced cocaine-induced behaviors. The antagonists and the SSRI, fluoxetine, did not alter the behaviors in comparison to that of saline-treated animals. These results provide evidence for an involvement of 5-HT1A receptors in the enhancing effect of fluoxetine and methysergide on cocaine-induced locomotor activity, rears, and head bobs, and suggest a stimulatory action of m




J Chromatogr B Biomed Sci Appl. 1997 Dec 19;704(1-2):259-63.
Quantification of fluoxetine and norfluoxetine serum levels by reversed-phase high-performance liquid chromatography with ultraviolet detection.

Holladay JW, Dewey MJ, Yoo SD.

College of Pharmacy, Nursing and Allied Health Sciences, Division of Pharmacy, Howard University, Washington, DC 20059, USA.

A rapid and sensitive high-performance liquid chromatography assay method was developed to determine serum fluoxetine and norfluoxetine levels by single extraction of 0.1 ml of serum with sodium hydroxide. The mobile phase (55% acetonitrile-45% distilled water containing 10 mM aqueous triethylamine) was used to separate fluoxetine and norfluoxetine (25-1000 ng/ml, using clomipramine as the internal standard) by ultraviolet detection at 226 nm. The inter- and intra-day variabilities of fluoxetine and norfluoxetine were 13-18%, and the recoveries of both drugs exceeded 89%. This assay method was applied to a pharmacokinetic disposition study of fluoxetine in mice.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9518159&dopt=Abstract fluoxetine




Br J Psychiatry. 1998 Feb;172:175-8.
Fluoxetine in breast-milk and developmental outcome of breast-fed infants.

Yoshida K, Smith B, Craggs M, Kumar RC.

Section of Perinatal Psychiatry, University of London, Denmark Hill.

BACKGROUND: Selective serotonin reuptake inhibitors are currently the most widely prescribed antidepressant drugs. There are only four published studies of breast-feeding mothers and their infants in which the mothers were taking fluoxetine. METHOD: Four mothers who took fluoxetine and their breast-fed infants were studied. Samples of plasma, breast-milk and urine were taken from the mothers and of plasma and urine from infants for assays of drug and metabolite concentrations. Bayley Scales of Infant Development were repeatedly used to assess cognitive and psychomotor development of the infants. RESULTS: Fluoxetine and norfluoxetine were detected in all samples of maternal plasma (range of total concentration 138-427 ng/ml) and in breast-milk (range 39-177 ng/ml). Amounts of both fluoxetine and norfluoxetine in infants' plasma and urine were below the lower limit of detection. All infants were observed to be developing normally and showed no abnormal findings on neurological examination. CONCLUSIONS: Much larger databases are needed but these four cases do not provide any evidence to suggest that women who are maintained on therapeutic doses of fluoxetine should discontinue breast-feeding their infants if they wish to breast-feed.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9519072&dopt=Abstract fluoxetine




Brain Res Mol Brain Res. 1998 Feb;54(1):64-73.
Serotonergic regulation of neuropeptide and glutamic acid decarboxylase mRNA levels in the rat striatum and globus pallidus: studies with fluoxetine and DOI.

Mijnster MJ, Galis-de Graaf Y, Voorn P.

Graduate School Neurosciences Amsterdam, Vrije Universiteit, Department of Anatomy and Embryology, The Netherlands.

The serotonergic regulation of neuropeptide and glutamic acid decarboxylase (GAD) mRNA level in the rat basal ganglia was investigated by determining the effects of chronic treatment with the serotonin uptake blocker fluoxetine and the serotonin 5-HT2 agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI). Fluoxetine (10 mg/kg) induced a reduction of preproenkephalin and GAD65 mRNA levels in the caudate-putamen and nucleus accumbens core and shell after 5 days of treatment. In addition, GAD65 mRNA levels were reduced in the globus pallidus. These changes appeared to be transient as they were not found after 15 days of fluoxetine treatment. DOI (7 mg/kg), administered for 9 days, induced a decrease of preprodynorphin mRNA levels in the caudate-putamen and the nucleus accumbens core and shell. No regional differentiation in the effects of fluoxetine and DOI was observed. Based on the present results, we propose that an increased 5-HT tone may reduce enkephalin and GABA mRNA levels in striatal regions and in the globus pallidus. Our results further show that preproenkephalin mRNA is not affected by chronic 5-HT2 receptor stimulation, indicating that the fluoxetine-induced decrease in preproenkephalin mRNA levels involves other 5-HT receptors than the 5-HT2 receptor. Preprodynorphin mRNA levels, on the other hand, were found to be reduced after chronic 5-HT2 receptors than stimulation. This observation, together with our previous finding that the 5-HT2 antagonist ritanserin tends to increase preprodynorphin mRNA levels, suggests a 5-HT2-mediated tonic inhibition of preprodynorphin mRNA levels.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9526047&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 1998 Mar;136(2):190-7.
Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test.

Reneric JP, Lucki I.

Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-2648, USA.

Because of clinical interest in the effects of antidepressant drugs that exert their effects on multiple neurotransmitter systems, the behavioral effects produced by combined treatment with an SSRI (fluoxetine) with a selective norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion) were examined in the forced swimming test (FST), a behavioral test in rodents that predicts the clinical activity of antidepressants. Three additional compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran, duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both reduced immobility in the FST, but desipramine increased only climbing behavior, whereas fluoxetine increased only swimming behavior. The combination of fluoxetine with desipramine or bupropion increased both climbing and swimming behaviors at certain doses, but higher doses of desipramine when combined with fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT reuptake inhibitors milnacipran and duloxetine reduced immobility and increased climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and increased swimming behavior, except at the highest dose tested (80 mg/kg), which increased both swimming and climbing behaviors. Thus, combining certain doses of pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST (climbing and swimming) that may reflect the activity of multiple neurotransmitters, especially the combination of enhanced 5-HT and DA activity. The combination of higher doses of desipramine with fluoxetine, or compounds with mixed activity at inhibiting NE and 5-HT reuptake, dem