Neuropsychopharmacology. 1999 Jun;20(6):628-39.
5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge.

Lerer B, Gelfin Y, Gorfine M, Allolio B, Lesch KP, Newman ME.

Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10327431&dopt=Abstract fluoxetine

ketthealth.com

Monoamine oxidase A (MAO-A) inhibition was investigated both in vitro and in vivo in rat brains by using the radioligand, 18F-fluoroclorgyline (N-[3-(2',4'-dichlorophenoxy)-2-18F-fluoropropyl]-N-methylpropa rgylamine). In vitro binding affinities of six compounds, clorgyline, Ro 41-1049, deprenyl, fluoxetine, norfluoxetine and citalopram, were studied. Fluoxetine and norfluoxetine showed in vitro affinities of 36.5 and 68 microM for MAO-A, respectively. Fluoxetine and norfluoxetine also significantly inhibited (more than 20%) the binding of the radioligand in vivo while citalopram and deprenyl showed very poor affinities in vitro for MAO-A and had no effect in vivo. The in vivo effects of the various drugs were directly comparable to their in vitro affinities for binding to MAO-A as seen in the correlation plot of percent control in vivo binding of 18F-fluoroclorgyline and binding affinity, -log IC50 (R2 = 0.979). An acute dose of 20 mg/kg of fluoxetine inhibited binding of 18F-fluoroclorgyline by more than 20%, while lower doses had some significant effects. These results provide evidence on the in vitro and in vivo inhibition of monoamine oxidase A by fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10051109&dopt=Abstract fluoxetine




Yonsei Med J. 1999 Apr;40(2):144-51.
Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat ventricular myocytes.

Park KS, Kong ID, Park KC, Lee JW.

Department of Physiology, Yonsei University Wonju College of Medicine, Korea.

The most common cardiovascular side effects of antidepressants are cardiac arrhythmias and orthostatic hypotension. Little is known, however, about the mechanisms by which these adverse reactions may occur, especially with regard to newer drugs such as fluoxetine. We hypothesized that these side effects may have an electrophysiological basis at the level of the cardiac myocyte. Thus, we investigated the effects of fluoxetine and other antidepressants on action potentials and ionic currents of rat ventricular myocytes using the amphotericin B perforated patch clamp technique. Fluoxetine (10 microM) prolonged the action potential duration (APD50) to 146.7 +/- 12.9% of control value without altering resting membrane potential. Fluoxetine and sertraline potently inhibited the L-type Ca2+ current (IC50 = 2.82 and 2.31 microM, respectively), but did not significantly modify the steady-state inactivation. Amitriptyline and imipramine had similar, but slightly weaker, effects (IC50 = 3.75 and 4.05 microM, respectively). Fluoxetine attenuated the peak transient outward K+ current and also altered current kinetics, as shown by accelerated decay. Fluoxetine did not change the voltage-dependence of the steady-state inactivation. Sertraline, amitriptyline and imipramine inhibited the transient outward K+ current with potencies very similar to fluoxetine. In contrast to the other antidepressants tested, trazodone weakly inhibited the Ca2+ and K+ currents and moclobemide had no detectable effect. Our comparative pharmacology data suggest that selective serotonin reuptake inhibitors, such as fluoxetine, are as potent as tricyclic antidepressants in inhibiting L-type Ca2+ and transient outward K+ currents. These inhibitory effects may contribute to cardiovascular

svm.vetmed.wisc.edu

Fluoxetine (Prozac) inhibits serotonin (5-HT) re-uptake. thereby enhancing serotonergic effects. Since serotonin is known to affect ventilation in a variety of circumstances, we investigated the effects of chronic serotonin re-uptake inhibition with fluoxetine on selected ventilatory responses including: (1) eupnea; (2) the hypercapnic ventilatory response at rest; (3) the exercise ventilatory response and (4) repeated trials of hypercapnic exercise. Ventilatory and arterial blood gases were measured in goats (n = 5) at rest, during steady-state treadmill exercise, and during successive rest/exercise trials with increased respiratory dead space (0.4-0.6 L). Fluoxetine was administered (> or = 4 weeks, 1 mg/kg, SQ, SID) and protocols were repeated. Following fluoxetine, PaCO2 was increased in most conditions studied; however, no differences were seen in exercise PaCO2 regulation or ventilatory responses pre- versus post-fluoxetine. We conclude that chronic fluoxetine slightly depresses respiratory control at rest, but, has minimal effects during exercise or with mild hypercapnia during rest or exercise in goats.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10344410&dopt=Abstract fluoxetine




J Pharm Pharmacol. 1998 Dec;50(12):1387-92.
Effects of fluoxetine and norfluoxetine on 5-hydroxytryptamine metabolism in blood platelets and brain after administration to rats.

Bourdeaux R, Desor D, Lehr PR, Younos C, Capolaghi B.

Laboratoire de Biochimie, CHR Metz-Thionville, Thionville, France.

The effects of intraperitoneal administration of fluoxetine (2.5, 5, 10 or 20 mg kg(-1)) and norfluoxetine (10 mg kg(-1)) on 5-hydroxytryptamine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) metabolism were examined in the blood platelets and brain of rats killed 3 h after a single dose. Several experiments were performed to evaluate the effect of norfluoxetine. Plasma 5-HT concentrations decreased significantly (48%) compared with control group results 3 h after administration of a single dose of fluoxetine (10 or 20 mg kg(-1)). Similar plasma 5-HT levels, 0.54+/-0.04 and 0.56+/-0.09 mg L(-1), respectively, were observed after administration of 10 mg kg(-1) fluoxetine or norfluoxetine. In the same way 5-HIAA levels in whole brain were similar, 0.36+/-0.03 and 0.34+/-0.01 microg(-1), respectively, after administration of fluoxetine or norfluoxetine. There was a good correlation between plasma and brain levels of fluoxetine (0.962) and norfluoxetine (0.957). The results suggest that fluoxetine and norfluoxetine lead to reduced levels of 5-HT in platelets and of 5-HIAA in the brain. Like the parent drug, norfluoxetine is a potent and selective inhibitor of 5-HT uptake.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10052854&dopt=Abstract fluoxetine




Pharmacol Res. 1999 Jun;39(6):451-4.
Effect of fluoxetine on maximal electroshock seizures in mice: acute vs chronic administration.

Raju SS, Noor AR, Gurthu S, Giriyappanavar CR, Acharya SB, Low HC, Quah SH.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Kubang Kerian, 16150, Malaysia.

There are no definite reports regarding the effects of chronic fluoxetine on animal models of epilepsy. Since chronically administered fluoxetine, in comparison to acutely administered fluoxetine has different effects on CNS, the present study was undertaken to investigate the effect of acute and chronic fluoxetine pretreatment, on a median anticonvulsant dose (ED50) of phenytoin in male ICR albino mice. Additionally, the effects of fluoxetine pretreatment on median convulsive current (CC50) in the presence and absence of phenytoin were investigated and results were compared. The maximal electroshock seizure (MES) test was used to estimate the ED50of phenytoin. The electroshock threshold test was used to estimate CC50. ED50and CC50values were calculated by probit analysis. The effects of the chronic and acute fluoxetine groups on the ED50of phenytoin were significantly different (P<0.05), and on CC50this difference was not statistically significant. Chronic fluoxetine insignificantly increased the ED50of phenytoin and decreased the CC50while acute fluoxetine decreased the ED50of phenytoin and increased the CC50. Our results indicate that chronic fluoxetine does not have an antiepileptic property and it may have dubious proconvulsant properties, contrary to acute fluoxetine. Copyright 1999 Academic Press.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10373242&dopt=Abstract fluoxetine




Eur J Pharmacol. 1999 May 7;372(1):65-73.
Role of protein kinase C and cAMP in fluoxetine effects on human T-cell proliferation.

Edgar VA, Sterin-Borda L, Cremaschi GA, Genaro AM.

Centro de Estudios Farmacologicos y Botanicos (CEFYBO), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, Argentina.

In this work, we studied the effect of fluoxetine on human T-lymphocyte proliferation using optimal and suboptimal concanavalin A concentrations. In particular, we analyzed the influence of fluoxetine on the kinases that are involved in intracellular signalling after stimulation with mitogens. We found that fluoxetine promoted the Ca2+ -mediated proteolysis of protein kinase C (PKC) and increased cyclic-AMP (cAMP) levels, thereby impairing lymphocyte proliferation, when optimal concanavalin A concentrations were used. In contrast, when suboptimal concanavalin A concentrations were used, fluoxetine only increased PKC translocation, without modifying cAMP levels, leading to T-cell proliferation. According to our results, fluoxetine has a dual effect on T-cell proliferation by modulating the PKC and protein kinase A pathways. This mechanism is thought to be mediated through Ca2+ mobilization.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10374716&dopt=Abstract fluoxetine




Brain Res. 1998 Jan 19;781(1-2):119-26.
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.

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




Encephale. 1998 Jan-Feb;24(1):57-61.
[Fluoxetine: relations between plasma concentration and therapeutic effects in 32 patients with major depression and treated with 20 mg/day]

[Article in French]

Bourdeaux R, Pannetier P, Younos C, Desor D, Lehr PR, Capolaghi B.

Laboratoire de Biochimie, CHR Metz-Thionville.

The aim of this clinical study was to investigate 32 melancholic patients treated by fluoxetine (20 mg/day). The clinical examination to evaluate the antidepressant effect of fluoxetine was realized by using the HDS/MES criteria. The patients were divided into three groups (responders, partial responders with or without a relapse, non responders) according to their clinical evolution during treatment. Fluoxetine and norfluoxetine were evaluated by HPLC after 3 weeks of treatment. In the present study, 53% of the patients have a positively reaction to the 21 day's treatment. Our results showed no correlation between the psychiatric scores and the plasma concentrations of fluoxetine and norfluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559305&dopt=Abstract fluoxetine