J Pharmacol Exp Ther. 2003 Mar;304(3):978-84.
Fluoxetine increases GABA(A) receptor activity through a novel modulatory site.

Robinson RT, Drafts BC, Fisher JL.

Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA.

Fluoxetine is a selective serotonin reuptake inhibitor used widely in the treatment of depression. In contrast to the proconvulsant effect of many antidepressants, fluoxetine has anticonvulsant activity. This property may be due in part to positive modulation of the GABA(A) receptors (GABARs), which mediate most fast inhibitory neurotransmission in the mammalian brain. We examined the effect of fluoxetine on the activity of recombinant GABARs transiently expressed in mammalian cells. Fluoxetine increased the response of the receptor to submaximal GABA concentrations but did not alter the maximum current amplitude. Sensitivity did not depend upon the beta- or gamma-subtype composition of the receptor when coexpressed with the alpha(1) subunit. Among the six alpha subtypes, only the alpha(5) subunit conferred reduced sensitivity to fluoxetine. The metabolite norfluoxetine was even more potent than fluoxetine. Mutations at residues in the alpha(5) subunit that alter its sensitivity to zinc or selective benzodiazepine derivatives did not affect potentiation by fluoxetine. This suggests that fluoxetine acts through a novel modulatory site on the GABAR. The direct positive modulation of GABARs by fluoxetine may be a factor in its anticonvulsant activity.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604672&dopt=Abstract fluoxetine




Turk Psikiyatri Derg. 2002 Winter;13(4):320-4.
[Ecchymosis associated with the use of fluoxetine: case report]

[Article in Turkish]

Mirsal H, Kalyoncu A, Pektas O.

Maltepe U Tip Fak, Psikiyatri AD, Istanbul.

Selective Serotonin Reuptake Inhibitors (SSRI) are well established in psychopharmacological therapy. SSRIs have been shown to be very effective in the treatment of depressive, anxiety and obsessive-compulsive disorders and have a favorable side effect profile. Although bleeding events are rare, there may be potentially severe hematologic complications following treatment with SSRIs. Fluoxetine has been reported to cause ecchymosis, bleeding and other hematologic problems. The aim of this article is to report a case of suspected fluoxetine-induced ecchymosis and to review the literature about this adverse effect. CASE SUMMARY: A 23-year-old woman was diagnosed with depressive disorder according to DSM-IV criteria and treated with fluoxetine 20 mg/day. After treatment for 10 weeks, the patient reported ecchymosis without any trauma. Her complete blood cell count, prothrombin time, partial thromboplastin time, bleeding time and other hematologic screening tests were within the normal limits. Her complete physical examination was also normal. After the medication was discontinued for 4 weeks, ecchymosis disappeared. A month later, the patient took fluoxetine for a week, and then the ecchymosis restarted. Fluoxetine was suspected to be the cause of these lesions. SSRIs cause these side effects by disrupting the normal platelet aggregation process through the blockade of serotonin uptake into platelets. For this reason, caution is recommended when using fluoxetine and other SSRIs in patients with thrombocytopenia or suspected platelet dysfunction.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12794649&dopt=Abstract fluoxetine




Methods Find Exp Clin Pharmacol. 2003 May;25(4):273-80.
Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/DA/serotoninergic pathways.

Singh VP, Jain NK, Kulkarni SK.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-A

feigerresearch.com

The aim of this study was to examine response and remission rates in outpatients treated with sertraline or fluoxetine who were suffering from two depression subtypes: anxious-depression and severe depression. Data were pooled from five double-blind studies comparing fluoxetine versus sertraline for the treatment of DSM-III-R or IV major depression. Clinical outcome was assessed using the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression-Improvement scale (CGI-I). One thousand and eighty-eight patients were randomized, with 654 (60%) meeting criteria for anxious depression and 212 (19%) meeting criteria for high severity depression. For the total sample, treatment response was similar for both sertraline and fluoxetine. In the high severity subgroup, the mean (+/-SD) HAM-D score at week 12 was 8.9+/-5.7 for sertraline and 10.8+/-6.9 for fluoxetine (P=0.07), and the mean (+/-SD) CGI-I score was 1.5+/-0.7 for sertraline and 2.0+/-1.1 for fluoxetine (P=0.005). CGI-I responder rates were 88% versus 71% (P=0.03) in the high severity subgroup, and 84% versus 79% (P=0.16) in the anxious-depression subgroup. Overall, sertraline and fluoxetine showed comparable antidepressant efficacy, although sertraline may offer an advantage in those patients with severe depression.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12817154&dopt=Abstract fluoxetine

if-pan.krakow.pl

The aim of the present study was to investigate the effect of the distribution interaction between thioridazine and fluoxetine in vivo. Experiments were carried out on male Wistar rats. Animals received thioridazine and fluoxetine separately or jointly, at a dose of 10 mg/kg ip. Concentrations of thioridazine and its metabolites and fluoxetine in the plasma and tissues were measured at 1 h after administration of the drugs (HPLC). Effects of distribution interactions were estimated on the basis of the calculated tissue/plasma and lysosome-poor/lysosome-rich tissue concentration ratios, considering the heart and muscles as lysosome-poor tissues and the lungs, liver and kidneys as lysosome-rich ones. Fluoxetine diminished the tissue/plasma concentration ratio of thioridazine for the lungs, but elevated this ratio for the muscles and heart. On the other hand, thioridazine elevated the brain/plasma and heart/plasma concentration ratios of fluoxetine. Consequently, the thioridazine lysosome-poor/lysosome-rich tissue concentration ratios significantly increased in the presence of fluoxetine. At the same time, thioridazine raised (or showed such a tendency) the heart/lysosome-rich tissue concentration ratios of fluoxetine, not changing significantly the muscles/lysosome-rich tissue concentration ratios of the antidepressant. The presented results provide evidence that the distribution interactions between thioridazine and fluoxetine observed in vitro occur also in vivo, leading to a shift of the drugs from organs rich in lysosomes to those poor in these organella, in particular to the heart. Thioridazine and fluoxetine mutually increased their heart/plasma and heart/lysosome-rich t




Br J Pharmacol. 2003 Jul;139(6):1111-8.
Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters.

Pariante CM, Kim RB, Makoff A, Kerwin RW.

Section of Clinical Neuropharmacology, PO 51, Institute of Psychiatry, King's College London, 1 Windsor Walk, Denmark Hill, London, SE5 8AF.

1. Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexamethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335-1343). 2. We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-glycoprotein activity in Caco-2 cells. 3. We now find that fluoxetine (1-10 micro M) enhances GR-mediated gene transcription in the presence of dexamethasone and cortisol (+140-170%), but not of corticosterone, and increases the intracellular accumulation of (3)H-cortisol (+5-15%), but not of (3)H-corticosterone. Moreover, fluoxetine (10 micro M) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4. Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12871829&dopt=Abstract fluoxetine




Eur J Neurosci. 2003 Aug;18(4):1021-7.
Methylenendioxyamphetamine produces serotonin nerve terminal loss and diminished behavioural and neurochemical responses to the antidepressant fluoxetine.

Harkin A, Shanahan E, Kelly JP, Connor TJ.

Department of Pharmacology, National University of Ireland, Galway, Ireland.

The effect of prior exposure to methylenedioxyamphetamine (MDA) on behavioural and neurochemical responses to fluoxetine were assessed in a rat model of antidepressant action. MDA (7.5 mg/kg, i.p.) was administered to rats twice daily for 4 consecutive days, and 4 weeks later the behavioural effect of fluoxetine (5 or 20 mg/kg; i.p. x 3) was examined in the modified rat forced-swimming test. In addition, the ability of fluoxetine to reduce serotonin (5-HT) metabolism was measured as an index of its efficacy in inhibiting 5-HT reuptake in vivo. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) produced a characteristic increase in swimming behaviour in the forced-swimming test. In contrast, fluoxetine-induced swimming was markedly attenuated in MDA-treated rats. MDA pretreatment resulted in 5-HT nerve terminal degeneration, indicated by reduced 5-HT and 5-HIAA concentrations in the frontal cortex, amygdala and hippocampus, and reduced [3H]paroxetine binding in the frontal cortex. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) decreased 5-HT metabolism (5-HIAA : 5-HT ratio) in the frontal cortex, amygdala and hippocampus. MDA pretreatment attenuated the ability of fluoxetine to reduce 5-HT metabolism in all brain regions examined. These findings are the first to demonstrate that prior exposure to the methylenedioxy-substituted amphetamine MDA results in diminished responsiveness to the antidepressant fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12925028&dopt=Abstract fluoxetine




Neurosci Lett. 2003 Oct 9;349(3):196-200.
Electrophysiological effects of acute and chronic olanzapine and fluoxetine in the rat prefrontal cortex.

Gronier BS, Rasmussen K.

Lilly Research Centre, Eli Lilly and Co., Windlesham, UK.

Since the prefrontal cortex (PFC) is thought to play an important role in depression and schizophrenia, we studied the effects of fluoxetine and olanzapine on PFC neurons in rats using extracellular, in vivo recordings. Acute or 5-day administration of olanzapine (1-10 mg/kg, iv or 20 mg/kg, sc) did not change the firing rate of PFC neurons. However, a 21-day treatment with olanzapine (20 mg/kg per day, sc) significantly increased the firing rate of PFC neurons and increased their responsiveness to the iontophoretic administration of the GABA(A) antagonist bicuculline. Acute administration of fluoxetine (10 mg/kg, iv) also did not change the firing rate of PFC neurons. However, a 21-day treatment with fluoxetine (10 mg/kg per day) significantly decreased the firing rate of PFC neurons and decreased their responsiveness to the iontophoretic administration of bicuculline. Co-administration of olanzapine (10 mg/kg per day, sc) during the last 5 days of a 21-day fluoxetine treatment (10 mg/kg per day) prevented the suppression of firing and decreased responsiveness to the iontophoretic administration of bicuculline of PFC neurons. In conclusion, chronic, but not acute, olanzapine treatment significantly enhanced the firing and excitability of PFC neurons. In addition, chronic, but not acute, fluoxetine treatment significantly suppressed the firing and excitability of PFC neurons. Further, short-term olanzapine treatment attenuated the suppression of firing and excitability of PFC neurons induced by chronic fluoxetine treatment. These effects of olanzapine, fluoxetine, and the olanzapine/fluoxetine combination in the PFC may play an important role in the beneficial therapeutic effect of these compounds in schizophrenia and depression and may have implications for the tre




Physiol Behav. 2003 Sep;79(4-5):719-24.
Fluoxetine treatment decreases territorial aggression in a coral reef fish.

Perreault HA, Semsar K, Godwin J.

Department of Zoology and W.M. Keck Center for Behavioral Biology, North Carolina State University, Box 7617, Raleigh, NC 27695-7617, USA.

Serotonin is an important neurotransmitter in the regulation of social interactions in many animals. Correlative studies in numerous vertebrate species, including fishes, indicate that aggressive males have lower relative serotonergic activity than less aggressive males. We used fluoxetine, a selective serotonin reuptake inhibitor, to experimentally enhance serotonergic neurotransmission in a territorial coral reef fish and test the role of this neurotransmitter in mediating aggressive behavior and dominance interactions. The bluehead wrasse, Thalassoma bifasciatum, has a complex social system in which large males aggressively defend spawning territories from intruders. In separate experiments, we tested the effects of chronic and acute fluoxetine treatments on aggressive behavior using a resident-intruder design. In a laboratory experiment, males treated daily with intraperitoneal fluoxetine injections for 2 weeks (6 microg/g bw) displayed fewer intruder chases than saline-treated controls. Chronically fluoxetine-treated males also showed lower levels of activity than saline controls prior to intruder trials. However, activity was not correlated with chases on an individual level, indicating the lower aggression displayed by fluoxetine-treated males was not due solely to general reductions in behavioral display. A field study exposed males to a confined territorial intruder following single intraperitoneal injections of fluoxetine (10 microg/g bw) or saline given to the same individual on different days. The frequency of aggressive chases following acute fluoxetine treatment was significantly lower than that following saline injections. This study experimentally supports the link between serotonin and aggr