Prozac
Effect of fluoxetine on melatonin in patients with seasonal affective disorder and matched controls.

Childs PA, Rodin I, Martin NJ, Allen NH, Plaskett L, Smythe PJ, Thompson C.

University Department of Psychiatry, Royal South Hants Hospital, Southampton.

BACKGROUND. The aim was to investigate the secretion profile of melatonin and seasonal affective disorder before and after treatment with fluoxetine. METHOD. A six-week case-controlled study with repeated overnight blood sampling was conducted. Ten patients fulfilling the criteria for major depressive disorder, seasonal type, with a 29-item Hamilton Depression Rating Scale (HDRS) score of at least 20 were compared with ten age- and sex-matched healthy controls in a clinical laboratory. The effects of fluoxetine (20 mg/day) on the HDRS and melatonin concentration were measured. RESULTS. Fluoxetine significantly reduced melatonin levels in both groups. There was no significant difference in melatonin secretion between the groups. CONCLUSIONS. The effect of fluoxetine differs from tricyclics and fluvoxamine, both of which increase melatonin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7728363&dopt=Abstract fluoxetine Prozac



Prozac
Growth-inhibitory effects of serotonin uptake inhibitors on human prostate carcinoma cell lines.

Abdul M, Logothetis CJ, Hoosein NM.

Department of Genitourinary Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.

Growth stimulation of a variety of cell types by the neurotransmitter serotonin has been reported. We have examined the effects of three serotonin-uptake inhibitors, 6-nitroquipazine, zimelidine and fluoxetine (Prozac, Eli Lilly Co., Indianapolis, Indiana) on human prostate carcinoma cell lines. In vitro, all 3 of these compounds inhibited the proliferation of PC-3, DU-145 and LNCaP cells in a dose-dependent manner. Also, all 3 compounds blocked the uptake of a radiolabeled analog of serotonin by the prostate carcinoma cell lines. The order of potency for inhibition of growth as well as for serotonin uptake was fluoxetine > zimelidine > 6-nitroquipazine. The growth of subcutaneous, PC-3 xenografts in athymic nude mice was significantly inhibited by fluoxetine. These results implicate biogenic amines such as serotonin in the growth of prostate carcinoma cells and indicate the potential use of serotonin-uptake inhibitors for the treatment of prostate cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7776439&dopt=Abstract fluoxetine Prozac



Prozac
[Central serotonin receptors and chronic treatment with selective serotonin reuptake inhibitors in the rat: comparative effects of fluoxetine and paroxetine]

[Article in French]

Le Poul E, Lima L, Laporte AM, Even C, Doucet E, Fattaccini CM, Laaris N, Hamon M, Lanfumey L.

INSERM U288, Faculte de Medecine Pitie-Salpetriere, Paris.

The hypothesis that a dysfunction of serotonergic neurotransmission is implicated in depression is supported by the clinical efficiency of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) in the treatment of depressive disorders. These drugs, such as fluoxetine and paroxetine, exert their antidepressant activity by increasing 5-HT concentration in the synaptic cleft and thus enhancing serotonergic neurotransmission. However, two to three weeks of treatment are necessary to see the first signs of clinical efficiency. Several hypothetical mechanisms have been put forward to account for this delay, taking into account pharmacokinetic considerations, neurotransmitter metabolism, and/or adaptive regulation of pre and/or post-synaptic receptors. The aim of this study was to look for such adaptive changes in the course of a 3-week treatment with fluoxetine (5 mg/kg/day, i.p.) or paroxetine (5 mg/kg/day, i.p.) in adult rats. In vitro binding and quantitative autoradiographic studies showed that neither 5-HT1A, 5-HT1B, 5-HT2A, nor 5-HT3 receptor binding sites in various brain areas were affected by these treatments. Furthermore, comparison of the specific binding of [3H]8-OH-DPAT to 5-HT1A receptors functionally coupled to G proteins with that of [3H]WAY 100635 to all 5-HT1A receptor binding sites (i.e. coupled and uncoupled with regard to G proteins) revealed no significant change in rats treated with either SSRI. Accordingly, the proportion of functional 5-HT1A receptors (i.e. those physically coupled to G proteins) appeared to remain unaltered all along a 3-week treatment with either fluoxetine or paroxetine. Nevertheless, in vitro electrophysiological recordings of serotonergic neurons in the dorsal raphe nucleus allowed the demonstration of a clearcut functional desensitization of somatodendritic 5-HT1A autoreceptors. Thus, the potency of the 5-HT1A autoreceptor agonist, 8-OH-DPAT, to depress the firing of serotonergic neurons in brain stem slices was significantly reduced as soon as after a 3-day treatment with either SSRI. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT1A autoreceptors then increased along the treatment, and was generally larger with fluoxetine than with paroxetine. As 5-HT1A autoreceptor desensitization can contribute to facilitate serotoninergic neurotransmission, the remarkable efficiency of fluoxetine to trigger this adaptive regulatory mechanism might account, at least partly, for its potent antidepressant activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7781583&dopt=Abstract fluoxetine Prozac



Prozac
Effect of acute fluoxetine treatment on the brain serotonin synthesis as measured by the alpha-methyl-L-tryptophan autoradiographic method.

Tsuiki K, Yamamoto YL, Diksic M.

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

The effect of treatment with acute fluoxetine, a serotonin reuptake inhibitor, on the rate of serotonin synthesis in the rat brain was studied through autoradiography following intravenous administration of alpha-methyl-L-[3H]tryptophan. The rate of serotonin synthesis in fluoxetine-treated rats was compared with the rate measured in sham-treated rats (saline injection). Results showed a significant increase in the rate of synthesis in the majority of cerebral structures examined. The greatest increase (given as a percentage of rates in control animals) in the rate of serotonin synthesis was observed in the substantia nigra compacta (344%), hippocampus-CA3 (337%), dorsal hippocampus (283%), and caudate-putamen (232%). Fluoxetine had a less significant effect on the rate of synthesis in the pineal body (44%). Data suggest that acute fluoxetine treatment (30 mg/kg, i.p.) enhances the rate of serotonin synthesis in all the structures of rat brain examined in this work.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7790867&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine and extrapyramidal side effects.

Coulter DM, Pillans PI.

University of Otago Medical School, Dunedin, New Zealand.

OBJECTIVE: The authors' goal was to determine whether fluoxetine is associated with extrapyramidal side effects. METHOD: They assessed the notifications of extrapyramidal manifestations in patients given fluoxetine in the New Zealand Intensive Medicines Monitoring Programme, a national system that monitored adverse reactions associated with fluoxetine over a 4-year period, and determined whether these adverse reactions were causally related to fluoxetine. RESULTS: In reports of adverse reactions in 5,555 patients given fluoxetine throughout New Zealand, there were 15 notifications of extrapyramidal events probably or possibly caused by fluoxetine. Fluoxetine was the only psychotropic agent used for seven of the 15 patients; two patients were also taking lithium, four were taking neuroleptics, two were taking tricyclic antidepressants, and one was taking metoclopramide. CONCLUSIONS: The authors conclude that fluoxetine may be associated with extrapyramidal reactions. These may occur with fluoxetine alone or fluoxetine may facilitate the reaction in patients receiving psychotropic medication or dopamine receptor blocking drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7802102&dopt=Abstract fluoxetine Prozac



Prozac
MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes.

Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramauge M, Courtin F, Pierre M.

Unite de Recherche Steroides et Systeme Nerveux, Unite 488 de l'Institut National de la Sante et de la Recherche Medicale (INSERM), 94276, Le Kremlin-Bicetre, France. mercier kb.inserm.fr

Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15456934&dopt=Abstract fluoxetine Prozac



Prozac
Evidence for catecholamine-depleting action of fluoxetine.

Patil MR, Satia MC, Mehta AA, Goyal RK.

Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad.

The present investigation was undertaken to study the interaction of fluoxetine with 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in rat anococcygeus muscle and vas-deferens. In rat anococcygeus muscle responses to NA were significantly potentiated after 30 min and 60 min incubation with fluoxetine (2.9 x 10(-9) M). The responses to 5-HT were however, inhibited after 30 min incubation with fluoxetine in this preparation. On rat vas-deferens also, the responses to NA were potentiated after 30 min incubation with fluoxetine. The response to 5-HT were not altered significantly. In rats pretreated with fluoxetine (5 mg/kg, ip) for seven days, the responses to NA were significantly potentiated in rat anococcygeus muscle. Whereas the responses to 5-HT and tyramine were significantly inhibited. The inhibited responses to 5-HT restored back to normal when the anococcygeus muscle was pre-incubated with NA for 30 min.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7814076&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine reduces inflammatory edema in the rat: involvement of the pituitary-adrenal axis.

Bianchi M, Sacerdote P, Panerai AE.

Department of Pharmacology, School of Medicine, University of Milano, Italy.

The acute effect of the non-tricyclic, pro-serotoninergic, antidepressant drug fluoxetine on inflammatory edema was evaluated in the rat. Fluoxetine significantly and dose dependently reduced the swelling induced by the injection of 10% brewer's yeast suspension in the hindpaw. Both adrenalectomy and hypophysectomy prevented the effect of fluoxetine. In contrast pretreatment with the corticotropin-releasing hormone antagonist alpha-helical CRH-(9-41) did not interfere with the anti-inflammatory action of fluoxetine. Moreover, the drug induced a significant increase of corticosterone plasma concentrations in vivo, whereas, in vitro, it did not stimulate beta-endorphin release from anterior pituitary cells. Our data suggest that fluoxetine exerts a potent anti-inflammatory action by inducing pituitary-adrenocortical activation via serotonin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7821365&dopt=Abstract fluoxetine Prozac