Prozac
Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens.

Ichikawa J, Kuroki T, Meltzer HY.

Department of Psychiatry, Vanderbilt University School of Medicine, Psychiatry Hospital at Vanderbilt, Nashville, TN 37212, USA.

The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24-28 days followed by 3-5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7 +/- 1.5 fmol/20 microl per 30 min, P = 0.019), and moderately decreased after chronic fluoxetine (6.5 +/- 0.6, P = 0.047), as compared to the vehicle controls (9.1 +/- 0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the D-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P = 0.002), but unchanged after chronic fluoxetine (P = 0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337 +/- 45 fmol/180 min, P = 0.005) and chronic fluoxetine (249 +/- 38, P = 0.57), as compared to the vehicle controls (178 +/- 29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9696403&dopt=Abstract fluoxetine Prozac



Prozac
Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors.

Maggi L, Palma E, Miledi R, Eusebi F.

Centro Ricerca Sperimentale Istituto Regina Elena, Roma, Italy.

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9702746&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine inhibits A-type potassium currents in primary cultured rat hippocampal neurons.

Choi JS, Choi BH, Ahn HS, Kim MJ, Han TH, Rhie DJ, Yoon SH, Jo YH, Kim MS, Hahn SJ.

Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.

The effects of fluoxetine (Prozac) on the transient A-currents (IA) in primary cultured hippocampal neurons were examined using the whole-cell patch clamp technique. Fluoxetine did not significantly decrease the peak amplitude of whole-cell K+ currents, but it accelerated the decay rate of inactivation, and thus decreased the current amplitude at the end of the pulse. For further analysis, IA and delayed rectifier K+ currents (IDR) were isolated from total K+ currents. Fluoxetine decreased IA (the integral of the outward current) in a concentration-dependent manner with an IC50 of 5.54 microM. Norfluoxetine, the major active metabolite of fluoxetine, was a more potent inhibitor of IA than was fluoxetine, with an IC50 of 0.90 microM. Fluoxetine (3 microM) inhibited IA in a voltage-dependent manner over the whole range of membrane potentials tested. Analysis of the time dependence of inhibition gave estimates of 34.72 microM(-1) s(-1) and 116.39 s(-1) for the rate constants of association and dissociation, respectively. The resulting apparent Kd was 3.35 microM, similar to the IC50 value obtained from the concentration-response curve. In current clamp configuration, fluoxetine (3 microM) induced depolarization of resting membrane potential and reduced the rate of action potential. Our results indicate that fluoxetine produces a concentration- and voltage-dependent inhibition of IA, and that this effect could affect the excitability of hippocampal neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15276879&dopt=Abstract fluoxetine Prozac



Prozac
In vivo evaluation of serotonergic agents and alpha-adrenergic blockers on premature ejaculation by inhibiting the seminal vesicle pressure response to electrical nerve stimulation.

Hsieh JT, Chang HC, Law HS, Hsieh CH, Cheng JT.

Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.

OBJECTIVE: To evaluate the effect of drugs on premature ejaculation using a rat animal model in which the seminal vesicle was electrically stimulated via its lesser splanchnic nerve and changes in the pressure response monitored. MATERIALS AND METHODS: Male Wistar rats (aged 12-14 weeks) were injected intravenously with prazosin and serotonergic agents (serotonin, clomipramine, fluoxetine, imipramine and indatraline) at various concentrations 10 min before electrical nerve stimulation (ENS) of the lesser splanchnic nerve; the initial increase in seminal vesicle pressure in response to ENS was then compared. RESULTS: The pressure response to ENS was reduced in the presence of prazosin or serotonergic agents. The mean (SEM) maximum inhibition values were 84.1 (8.9%) by fluoxetine at 0.1 mg/kg, 67.9 (8.7)% by prazosin at 0.1 mg/kg, 60.9 (11.0)% by serotonin at 3 mg/kg, 54.9 (4.6)% by clomipramine at 3 mg/kg, 30.0 (11.0)% by imipramine at 0.1 mg/kg, and 20.9 (4.3)% by indatraline at 0.1 mg/kg. From the concentration-response curve, the potency of prazosin was lower than that of fluoxetine, but was higher than that of serotonin or clomipramine. CONCLUSIONS: Like serotonin, fluoxetine and clomipramine can reduce the pressure response of the seminal vesicle to ENS. Among these inhibitory agents, including prazosin, fluoxetine was the most effective and may be valuable for the clinical treatment of ejaculatory dysfunction in man.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9722759&dopt=Abstract fluoxetine Prozac



Prozac
Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat.

Malone DT, Taylor DA.

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

1. It has been suggested that the dose of delta9-tetrahydrocannabinol (delta9-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by delta4-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response. 2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg(-1) delta9-THC; maximum decreases being 0.8+/-0.2 degrees C to 2.9+/-0.3 degrees C. This hypothermic response was attenuated by the cannabinoid CB1 receptor antagonist SR 141716. 3. Fluoxetine (10 mg kg(-1) i.p.) alone caused a decrease in body temperature of 0.6+/-0.1 degrees C (n=32, P < 0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg(-1) i.p.) 40 min before delta9-THC significantly reduced the delta9-THC-induced hypothermia (n=7-8, P < 0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after delta9-THC significantly potentiated the delta9-THC-induced hypothermia, producing a maximum decrease of 3.2+/-0.3 degrees C. 4. It is suggested that the effect of fluoxetine on the delta9-THC-induced hypothermic response is dependent on the time of its administration relative to that of delta9-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the delta9-THC-induced hypothermia. Conversely, when fluoxetine is administered after delta9-THC, the reuptake block is thought to potentiate the already activated serotonergic system, hence potentiating the delta9-THC-induced hypothermia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9723953&dopt=Abstract fluoxetine Prozac



Prozac
Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment.

Caberlotto L, Fuxe K, Overstreet DH, Gerrard P, Hurd YL.

Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institute, S-171 75, Stockholm, Sweden.

To investigate the possible link between neuropeptide Y (NPY) and depression, we analyzed NPY and its receptors in different limbic-related regions in the Flinder sensitive line (FSL), a genetic animal model of depression. In situ hybridization histochemistry was used to measure mRNA expression levels of NPY and NPY receptors, Y1 and Y2, in the FSL as compared to the control Flinder resistant Line rats (FRL). In the FSL rats, NPY mRNA expression levels were significantly decreased in the nucleus accumbens and CA regions, but increased in the arcuate nucleus and anterior cingulate cortex. Y1 receptor mRNA expression was decreased in different cortical regions (retrosplenial, anterior cingulate, and occipital) and in the hippocampal dentate gyrus. Y2 mRNA expression levels did not differ between FSL and FRL animals. The effect of the antidepressant drug fluoxetine (a serotonin reuptake inhibitor) in the two rat strains was also studied. There was an increase of the NPY mRNA hybridization signal in the arcuate nucleus of both strains following the antidepressant treatment (10 micromol/kg; daily for 14 days). However, in other brain regions, fluoxetine administration caused a differential effect on the induction of NPY-related genes in the two rat strains: in the CA region and dentate gyrus NPY mRNA expression was increased in the FSL, but decreased in the FRL. In contrast, Y1 mRNA levels tended to be decreased by fluoxetine in the nucleus accumbens of the FSL rats, but increased in the FRL. These findings suggest an involvement of the Y1, but not the Y2, receptor subtype in depressive disorder. Overall, the results appear to sustain the importance of the FSL rats as an animal model of depression in view of the impairment of NPY genes and the ability of fluoxetine treatment to normalize NPY-related gene expression selectively in this strain. Copyright 1998 Elsevier Science B.V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9729278&dopt=Abstract fluoxetine Prozac



Prozac
Prenatal exposure to fluoxetine (Prozac) produces site-specific and age-dependent alterations in brain serotonin transporters in rat progeny: evidence from autoradiographic studies.

Cabrera-Vera TM, Battaglia G.

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

The present study provides the first autoradiographic evidence of age-dependent regional changes in the density of serotonin (5-HT) transporters in offspring following prenatal exposure to fluoxetine. Pregnant rats received either saline or fluoxetine (10 mg/kg, s.c.) daily from gestational day 13 through 20. The density of [3H]citalopram-labeled 5-HT transporters was determined in forebrain regions and in midbrain raphe nuclei of prepubescent and adult male offspring. Brain regions representing integral components of the limbic system were particularly sensitive to the prenatal treatment. For example, prenatal fluoxetine exposure significantly altered the density of 5-HT transporters in subregions of the hypothalamus (dorsomedial nucleus, -21%; lateral hypothalamus, +21%), hippocampus (CA2, +47%; CA3, +38%), and amygdala (basolateral nucleus, +32%; medial nucleus, +44%) in prepubescent offspring. However, 5-HT transporter density in the dorsal and median raphe was unaltered in this same group of offspring. In adult offspring, 5-HT transporter densities, in all brain regions examined, were not significantly altered by prenatal exposure to fluoxetine. The present study also identifies significant age-related differences in 5-HT transporter densities between prepubescent and adult control offspring. For example, in adult control offspring, densities of 5-HT transporters were significantly greater in the cingulate cortex (+33%), basolateral amygdala (+58%), and CA1 area of the hippocampus (+78%); but significantly lower in the temporal cortex (-65%) and median raphe (-25%). The age-dependent and site-specific alterations in the density of 5-HT transporters suggests that either 5-HT innervation and/or 5-HT neuron function in various forebrain regions may be altered by prenatal exposure to fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9732413&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine induces the transcription of genes encoding c-fos, corticotropin-releasing factor and its type 1 receptor in rat brain.

Torres G, Horowitz JM, Laflamme N, Rivest S.

Department of Psychology, State University of New York at Buffalo, 14260, USA.

Fluoxetine is a serotonin re-uptake blocker commonly used to treat endogenous depression. The present experiments were carried out to assess the effects of fluoxetine on c-fos induction throughout the rat brain. In addition, intron-directed in situ hybridization analysis was used to examine fluoxetine regulation of corticotropin-releasing factor heteronuclear gene transcription in the paraventricular nucleus of the hypothalamus. Because the actions of corticotropin-releasing factor are mediated by membrane-bound corticotropin-releasing factor type 1 receptors, we also evaluated the stimulation of such receptors after acute fluoxetine exposure. The immediate-early gene, c-fos, was markedly induced in several telencephalic and diencephalic brain structures. For instance, a strong hybridized signal was apparent 30 min after fluoxetine (10 mg/kg; intraperitoneal) administration in the caudate putamen, septal nucleus, bed nucleus of stria terminalis, anterodorsal preoptic area, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus and posterior hypothalamic nucleus. In addition, c-fos-expressing neurons were also evident in discrete amygdaloid nuclei. This nuclear induction was brief in duration, as levels of the immediate-early gene were mostly undetectable 90 min after drug administration. In contrast to the extensive induction of c-fos by fluoxetine throughout the brain parenchyma, elevation of corticotropin-releasing factor heteronuclear RNA levels were confined exclusively to neurosecretory nerve cells of the paraventricular nucleus, with peak levels detected 30 min after fluoxetine exposure. Therefore, the time-course of corticotropin-releasing factor heteronuclear RNA closely paralleled that of c-fos. Significant changes in corticotropin-releasing factor type 1 receptor messenger RNA levels were also observed in the paraventricular nucleus but with a slow incremental biosynthesis of the receptor messenger RNA, as high levels were discernible only 360 min after fluoxetine treatment. Finally, we failed to detect sex-related differences in the acute response to fluoxetine, as both female and male rat brains showed a comparable induction of c-fos, corticotropin-releasing factor heteronuclear RNA and corticotropin-releasing factor type 1 receptor expression within parvocellular neurosecretory nerve cells that govern the stress response. All of these findings are discussed in terms of specific sequences of nuclear events that couple fluoxetine-based serotonin input with changes in gene expression in selective neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9740405&dopt=Abstract fluoxetine Prozac