Prozac
An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress.

Page ME, Abercrombie ED.

Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102, USA.

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9165497&dopt=Abstract fluoxetine Prozac



Prozac
Effects of first-trimester fluoxetine exposure on the newborn.

Goldstein DJ, Corbin LA, Sundell KL.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

OBJECTIVE: To determine whether first-trimester exposure to fluoxetine, a selective serotonin reuptake inhibitor commonly used to treat depression and obsessive-compulsive disorders, is associated with increased frequency of fetal malformations. METHODS: We evaluated outcomes of all pregnancies identified prospectively with confirmed first-trimester fluoxetine exposure contained in the Eli Lilly and Company worldwide fluoxetine pregnancy registry. These outcomes were compared with historic reports of newborn surveys. RESULTS: Outcomes were available for 796 pregnancies, 37 from fluoxetine clinical trials and 759 from spontaneous reports. Spontaneous abortions were reported in 110 of the 796 (13.8%) pregnancies. Of the remaining 686, malformations, deformations, and disruptions, including those identified after the perinatal period, were reported in 34 (5.0%). No consistent or recurring pattern of abnormalities was observed. CONCLUSION: Based on comparison with historic reports of newborn surveys, it is unlikely that maternal fluoxetine use during the first trimester of pregnancy results in increased risk of fetal malformations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9166307&dopt=Abstract fluoxetine Prozac



Prozac
Gender based response to fluoxetine hydrochloride medication in endogenous depression.

Bano S, Akhter S, Afridi MI.

Department of Biochemistry, University of Karachi, Karachi. saminbpk yahoo.com

OBJECTIVE: To determine the gender based response to fluoxetine HCl medication in relation to tryptophan metabolism in depressed patients. DESIGN: A comparative, analytical study. PLACE AND DURATION OF STUDY: Clinical Biochemistry and Psychopharmacology Research Unit, Department of Biochemistry, University of Karachi during the year 2002 to 2003. SUBJECTS AND METHODS: Sixteen adults depressed patients who were not having any other major comorbidity were selected from the outpatients department of local psychiatric clinic for the study. They were subjected to a semi-structured interview for associated clinical characteristics and diagnosis of depression according to ICD-10 criteria. A control group of normal health male and female individuals was identified for comparison with the depressed group.All the depressed patients were treated with fluoxetine hydrochloride (Prozac 20 mg/day) for four weeks. Healthy individual's data was compared with the depressed group and evaluated for gender based response to fluoxetine HCl medication. RESULTS: Significant decreases were found in total tryptophan concentrations (33 %, p<0.01,56%, p<0.01) in depressed male and female patients respectively, in contrast, serum cortisol levels were increased by 68% and 98% in male and female depressed patients respectively as compared to healthy controls. Significant increases (23%, p<0.05) in albumin levels were found in females only. Four weeks treatment of male and female depressed group by Fluoxetine HCL (Prozac) 20 mg/kg/day, increased serum total tryptophan concentrations significantly by 32% (p<0.05) in males and by 83% (p<0.01) in females. Serum-free tryptophan concentrations were increased by 22% (p<0.05) in males only. In contrast serum cortisol concentrations were decreased by 31% (p<0.01) and 45.35% (p<0.01) in males and females respectively. CONCLUSION: Increases in tryptophan and decreases in cortisol concentrations were greater in females which may contribute to better response of the drug in females.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15228850&dopt=Abstract fluoxetine Prozac



Prozac
Direct analysis of fluoxetine and norfluoxetine in plasma by gas chromatography with nitrogen-phosphorus detection.

Fontanille P, Jourdil N, Villier C, Bessard G.

Laboratoire de Pharmacologie, Centre Hospitalier Universitaire de Grenoble, France.

A quantitative method for the simultaneous GC resolution and detection of fluoxetine and his metabolite norfluoxetine in human plasma was developed. The procedure required 1.0 ml of plasma, extraction with a mixed organic solvent and injection into a capillary gas chromatograph with an OV-1 fused-silica column coupled to a nitrogen-phosphorus detector. The calibration curves were linear over the range 5-3000 ng/ml. The detection limits were 0.3 and 2 ng/ml for fluoxetine and norfluoxetine, respectively. The assay is suitable for routine analysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9188822&dopt=Abstract fluoxetine Prozac



Prozac
S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT)1A receptors: I. Interaction with cloned human (h)5-HT1A, dopamine hD2/hD3 and h alpha2A-adrenergic receptors in relation to modulation of cortical monoamine release and activity in models of potential antidepressant activity.

Millan MJ, Newman-Tancredi A, Rivet JM, Brocco M, Lacroix P, Audinot V, Cistarelli L, Gobert A.

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, France.

The novel, potential anxiolytic, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine), is an agonist and antagonist (weak partial agonist) at pre- and postsynaptic serotonin (5-HT)1A receptors, respectively. Herein, we characterized its influence on dialysate levels of 5-HT, dopamine (DA) and NAD simultaneously determined in single samples of the frontal cortex (FCX) of freely moving rats, and compared its activity in several other models of potential antidepressant (AD) properties with those of the 5-HT reuptake inhibitor (SSRI), fluoxetine. S 15535 displayed high affinity at cloned human (h) 5-HT1A receptors (Ki = 0.7 nM) and >250-fold lower affinity at cloned hD2 (400 nM), hD3 (248 nM) and h alpha2A-adrenergic (AR) (190 nM) receptors. S 15535 (0.08-5.0 mg/kg s.c.) markedly and dose-dependently suppressed dialysate levels of 5-HT in the FCX, nucleus accumbens and striatum of freely moving rats, whereas fluoxetine (10.0 mg/kg s.c.) elevated levels of 5-HT in each structure. In contrast to 5-HT, dialysate levels of DA and NAD in the FCX were dose-dependently increased by S 15535, and this effect was mimicked by fluoxetine. The influence of S 15535 and fluoxetine on FCX levels of DA was regionally specific inasmuch as dialysate levels of DA in the accumbens and striatum were not modified. The selective 5-HT1A antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (0.16) transiently elicited a slight increase in cortical levels of 5-HT, an action opposite to that of S 15535. Further, in the presence of WAY 100,635 (0.16), the influence of S 15535 (0.63) on cortical levels of 5-HT, DA and NAD was markedly attenuated. Upon chronic administration of S 15535 or fluoxetine (10.0 mg/kg s.c. daily for 14 days, in each case), there was no significant alteration in the density of beta-AR receptors in the FCX. However, in contrast to fluoxetine, S 15535 elicited a significant (25%) decrease in the density (Bmax) of 5-HT2A receptors labeled by [3H]ketanserin in the cortex; there was no alteration in Kd. In a learned helplessness paradigm in rats, S 15535 (0.63-40.0 mg/kg p.o.) markedly reduced escape deficits on each of three consecutive days of testing. Fluoxetine (2.0-8.0 mg/kg i.p.) was also active in each session, but presented a biphasic dose-response curve. Finally, under the conditions used, neither S 15535 (0.63-10.0) nor fluoxetine (0.63-10.0) decreased immobility time in the forced swim test. In conclusion, S 15535 is a selective ligand of cloned, h5-HT1A receptors. Its agonist actions at 5-HT1A autoreceptors underlie its ability to decrease extracellular levels of 5-HT in the FCX, and likely contribute to the increase in extracellular levels of DA and NAD evoked by S 15535 in this structure. Further, S 15535 is active in several other, although not all, models of potential AD activity. Thus, although S 15535 is under development as an anxiolytic agent, a further characterization of its putative AD actions would be of interest.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9223549&dopt=Abstract fluoxetine Prozac



Prozac
Interaction between the forced swimming test and fluoxetine treatment on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat.

Kirby LG, Lucki I.

Institute of Neurological Sciences, University of Pennsylvania, Philadelphia 19104-2649, USA.

We used in vivo microdialysis to examine extracellular levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and the lateral septum during the forced swimming test, (FST) a behavioral test conducted in rats that is commonly used to predict the effect of antidepressant drugs. The forced swimming test consisted of a 15-min pretest swim and a 5-min test swim 24 hr later. The antidepressant fluoxetine (20 mg/kg s.c.) or saline was administered 23.5, 5 and 1 hr before the test swim. In the striatum, the pretest swim increased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but slightly decreased striatal 5-HT in fluoxetine-treated rats. In the lateral septum, the pretest swim decreased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but decreased lateral septum 5-HT in fluoxetine-treated rats. Ratings of behavior showed that fluoxetine treatment increased swimming behavior and decreased immobility during the test swim. Immobility was positively correlated and swimming was negatively correlated with changes in extracellular 5-HT in the lateral septum but not in the striatum. Therefore, fluoxetine treatment altered adaptation of the regional response of extracellular 5-HT ordinarily produced in the FST, reversing the 5-HT response to the initial swim in the striatum and restoring the response to the initial swim in the lateral septum.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9262365&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine reduces saccharin-induced elevation of fluid intake in alcohol-preferring Fawn-Hooded rats.

Kampov-Polevoy AB, Rezvani AH.

Skipper Bowles Center for Alcohol Studies, University of North Carolina School of Medicine at Chapel Hill 27599-7178, USA.

Previous work has established that saccharin and alcohol intakes are highly correlated in a variety of rat strains. In addition, it has been shown that alcohol-preferring rats consume saccharin beyond the limit of their normal daily fluid intake (DFI). It has been hypothesized that alcohol-preferring rats have impaired control over consumption of reinforcing substances, which may be related to a deficiency of brain serotonin. In the present study, we examined the effect of the serotonin reuptake inhibitor fluoxetine (2.5, 5.0, 10.0 mg/kg, IP, twice a day) on saccharin intake in alcohol-preferring Fawn-Hooded (FH) rats. It was confirmed that alcohol preferring FH rats almost triple their DFI when saccharin/water choice was introduced. Treatment with fluoxetine resulted in a dose-dependent decrease in saccharin intake to, but not below, the normal level of their DFI. No significant effects of fluoxetine on water intake were observed. Despite a significant (up to 69%) decrease in saccharin intake, only a minimal reduction (< 4%) in saccharin preference occurred. We conclude that fluoxetine reduces the exessive elevation of fluid intake observed at the presence of the palatable saccharin solution in Fawn-Hooded rats. These findings may provide more evidence for the involvement of the serotonergic system in the brain in exessive drinking of rewarding substances.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9264069&dopt=Abstract fluoxetine Prozac



Prozac
Local cerebral metabolic effects of the novel cocaine analog, WF-31: comparisons to fluoxetine.

Porrino LJ, Miller M, Hedgecock AA, Thornley C, Matasi JJ, Davies HM.

Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157, USA. lporrino bgsm.edu

The effects of the acute administration of the selective serotonin uptake inhibitor, fluoxetine, on rates of local cerebral glucose utilization in rats were compared to those of the novel cocaine analog, [2beta-propanoyl-3beta-(4-isopropylphenyl)-tropane, WF-31, which has greater affinity for serotonin than dopamine transporters, using the quantitative autoradiographic 2-[14C]deoxyglucose method. Locomotor activity was assessed simultaneously. Fluoxetine administration resulted in dose-dependent decreases in locomotor behavior, as well as widespread reductions in rates of metabolic activity in brain areas including raphe nuclei, dorsal and ventral striatum, amygdala, hippocampus, limbic cortex, and thalamus. These effects were largely concentrated in brain regions containing high densities of serotonin transporters as revealed by in vitro autoradiography. In contrast, the acute administration of WF-31 produced more discrete changes in metabolic activity that were localized within the raphe nuclei and in portions of the hippocampal formation. Blockade of WF-31's dopaminergic effects by pretreatment with the antagonist, alpha-flupenthixol, resulted in a pattern of metabolic changes that closely resembled that observed with fluoxetine. These data suggest that the alterations in functional activity produced by both fluoxetine and WF-31 are largely the result of actions on serotonergic systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9268062&dopt=Abstract fluoxetine Prozac