Prozac
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 methysergide at the 5-HT1A receptor. In addition, some of the actions may also be mediated by activation of the 5-HT2A receptor and/or inhibition of the 5-HT2C receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9512061&dopt=Abstract fluoxetine Prozac



Prozac
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.

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



Prozac
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.

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



Prozac
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.

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



Prozac
Reproductive assessment of Japanese medaka (Oryzias latipes) following a four-week fluoxetine (SSRI) exposure.

Foran CM, Weston J, Slattery M, Brooks BW, Huggett DB.

Department of Biology, West Virginia University, Morgantown 26506-6057, USA. cmforan mail.wvu.edu

The occurrence of environmental pharmaceutical products has recently received considerable attention, but impacts on the aquatic environment are largely unknown. Fluoxetine is a widely prescribed antidepressant and acts physiologically as a selective serotonin reuptake inhibitor (SSRI). To determine its potential to disrupt teleost reproductive function, Japanese medaka (Oryzias latipes) were exposed to fluoxetine at aqueous nominal concentrations of 0, 0.1, 0.5, 1 and 5 microg/L for 4 weeks. The last 14 days of this exposure included a reproductive assessment in which no significant changes were observed in egg production, rate of fertilization and spawning, or hatching success of fertilized eggs. A low incidence (1.97-2.53%; 4.02-5.16-fold greater than controls) of developmental abnormalities was observed in offspring from all fluoxetine treatments. Adult gonadal somatic index, hepatic vitellogenin, and ex vivo gonadal steroidogenesis were also unaffected. Circulating plasma estradiol levels in females were significantly increased by 0.1 and 0.5 microg/L treatments. Our study provides novel information on fish biochemical, physiological, and reproduction responses to environmentally realistic fluoxetine concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15253049&dopt=Abstract fluoxetine Prozac



Prozac
Preweaning cocaine administration alters the adult response to quipazine: comparison with fluoxetine.

Dow-Edwards DL.

Department of Pharmacology, State University of New York, Health Science Center, Brooklyn 11203, USA. ddow-edw netmail.hscbklyn.edu

This study investigated whether exposure to cocaine during the preweaning period affects the behavioral response to administration of a challenge dose of quipazine, a relatively nonselective serotonin (5-HT) mixed agonist/antagonist, in adulthood. To determine whether selective inhibition of the 5-HT transporter during the preweaning period would produce a cocaine-like pattern of effects, another group of rats was given fluoxetine, a highly selective and potent inhibitor of the 5-HT transporter, and was tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg cocaine HCl (82.5 mumol/kg), 25 mg/kg fluoxetine HCl (72.3 mumol/kg), or vehicle subcutaneous (s.c.) during postnatal days 11-20. Both treatments reduced weight gain during the injection period only. At 60 days of age, subjects were administered a single dose of quipazine (0, 0.4, or 1.0 mg/kg, s.c.) and placed in the Accuscan activity monitor for 1 h of behavioral recording. Overall, distance traveled, vertical activity, and time in the center of the chamber decreased during the initial time blocks of the session and vertical activity decreased with increasing doses of quipazine. Females in general showed greater overall activity levels than males as well as greater responsivity to quipazine. Preweaning cocaine exposure produced different effects in males and females. In males, cocaine enhanced the response to quipazine for vertical activity whereas it had no effect on quipazine-induced alterations on the other two behaviors. On the other hand, cocaine-treated females showed dampened dose-related quipazine responses across all behavioral measures. Fluoxetine administration produced a dampening of the quipazine effect for vertical activity and distance traveled in males and females. Therefore, these data indicate that cocaine administration during the preweaning period of development produced an increase in the effect of a serotonergic drug to alter vertical activity in males and a global dampening of the behavioral responses to that same drug in females. Preweaning fluoxetine treatment produced effects that resembled those produced by cocaine in females, a dampening of serotonergic responsivity, along with an overall decrease in locomotor activity. Because the majority of effects are seen during the initial portion of the behavioral session, a time of heightened activity in response to a novel environment, the data suggest that inhibition of the 5-HT transporter during the preweaning period alters serotonergic influences over novelty-induced activity but that brief periods of inhibition or other actions of cocaine, such as those at the catecholamine transporters, prevent this from happening, particularly in males.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9536459&dopt=Abstract fluoxetine Prozac



Prozac
An in vitro evaluation of fluoxetine adsorption by activated charcoal and desorption upon addition of polyethylene glycol-electrolyte lavage solution.

Atta-Politou J, Kolioliou M, Havariotou M, Koutselinis A, Koupparis MA.

University of Athens, Greece.

BACKGROUND: In drug overdoses, treatment with activated charcoal is frequently used because of its adsorptive properties. Recently, whole-bowel irrigation with polyethylene glycol-electrolyte lavage solution has been used as a gastrointestinal decontamination procedure for ingestions of toxins not well adsorbed to activated charcoal and for toxins with a delayed absorption phase, although well adsorbed to activated charcoal. While a combined approach using activated charcoal and whole-bowel irrigation could theoretically enhance the efficacy of both modalities, this improvement remains speculative, since data demonstrating its clinical advantage in overdose treatment are lacking. Fluoxetine, a selective serotonin uptake inhibitor, is one of the most frequently prescribed antidepressants. Fluoxetine is well adsorbed onto activated charcoal. This in vitro investigation was undertaken to study: a) the effect of polyethylene glycol, as well as polyethylene glycol-electrolyte lavage solution, on the adsorption of fluoxetine to laboratory grade-activated charcoal and a commercial activated charcoal formulation (Carbomix powder) in simulated gastric (pH= 1.2) and intestinal (pH=7.2) fluid environment; b) whether the order of polyethylene glycol-electrolyte lavage solution addition would have any effect on the adsorption of fluoxetine to activated charcoal. METHODS: Adsorption of fluoxetine to charcoal in the presence of polyethylene glycol was examined: a) by the simultaneous addition of polyethylene glycol and charcoal to fluoxetine solution and b) by the addition of charcoal to fluoxetine solution and subsequent addition of polyethylene glycol. In both cases, the slurries were incubated at 37 degrees C for 1 hour and filtered. Free fluoxetine concentration was determined in the diluted filtrate by a reversed-phase high-performance liquid chromatography method. RESULTS: The amount of fluoxetine adsorbed to activated charcoal (or Carbomix) was dramatically decreased at gastric and intestinal pH by the presence of polyethylene glycol or polyethylene glycol-electrolyte lavage solution added either concurrently or sequentially to activated charcoal. CONCLUSIONS: In cases of fluoxetine overdose, administration of activated charcoal is recommended, while a combined approach using activated charcoal and whole-bowel irrigation with polyethylene glycol-electrolyte lavage solution is not recommended since it causes a significant desorption of the drug from activated charcoal.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9541057&dopt=Abstract fluoxetine Prozac



Prozac
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, demonstrated effects similar to those of desipramine alone and may reflect inhibition of the expression of serotonergic antidepressant behavioral effects by selective NE reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9551776&dopt=Abstract fluoxetine Prozac