J Clin Psychiatry. 1985 Mar;46(3 Pt 2):14-9.
Fluoxetine: clinical pharmacology and physiologic disposition.

Lemberger L, Bergstrom RF, Wolen RL, Farid NA, Enas GG, Aronoff GR.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of 14C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiple doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects.

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J Clin Psychiatry. 1985 Mar;46(3 Pt 2):7-13.
The pharmacologic profile of fluoxetine.

Stark P, Fuller RW, Wong DT.

Fluoxetine is a selective inhibitor of serotonin uptake in vitro. Unlike many antidepressant drugs, fluoxetine has little affinity for muscarinic, histaminic H1, serotonergic 5-HT1 or 5-HT2, or noradrenergic alpha 1 or alpha 2 receptors on rat brain membranes in vitro. Fluoxetine inhibits serotonin uptake in vivo without affecting norepinephrine uptake. Neuroendocrine and behavioral consequences of enhanced serotonergic function resulting from fluoxetine's inhibition of serotonin uptake in vivo are described. Fluoxetine is relatively nontoxic in several animal species. The specificity of action of fluoxetine makes it a good candidate as an antidepressant drug.

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Pharmacol Biochem Behav. 1982 Sep;17(3):435-43.
Effects of central and peripheral pretreatment with fluoxetine in gustatory conditioning.

Lorden JF, Nunn WB.

The administration of fluoxetine, a relatively specific serotonin uptake inhibitor, an hour prior to a taste-drug pairing was shown to attenuate the acquisition of taste aversions in a dose-dependent manner. Desipramine which is less effective than fluoxetine in blocking the reuptake of serotonin was also less potent in reducing the magnitude of taste aversions. Depletion of forebrain serotonin by lesions of the dorsal and median raphe nuclei or of norepinephrine by lesions of the dorsal noradrenergic bundle failed to prevent the pretreatment effect produced by either fluoxetine or desipramine. Rats with raphe lesions consistently consumed less of the taste paired with lithium than did control animals; however, this decreased intake occurred under both drug and saline pretreatment conditions, suggesting an increased sensitivity to the taste-lithium pairing rather than a diminution of the pretreatment effect. Rats with dorsal bundle lesions failed to differentiate between drug and saline pretreatment, consuming similar amounts under both conditions. These findings as well as the observation that intraventricular administration of fluoxetine did not produce a pretreatment effect suggest that forebrain serotonergic systems are not the critical site of action for the production of pretreatment effects by monoamine uptake inhibitors. Instead, the hypothesis that the peripheral effects of fluoxetine have a stimulus value that acts by way of an associative mechanism to attenuate gustatory conditioning must be considered.

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Clin Pharmacol Ther. 1984 Jul;36(1):138-44.
Fluoxetine kinetics and protein binding in normal and impaired renal function.

Aronoff GR, Bergstrom RF, Pottratz ST, Sloan RS, Wolen RL, Lemberger L.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

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Eur J Pharmacol. 1986 Feb 11;121(1):65-71.
Antidepressants and protein kinases: inhibition of Ca2+-regulated myosin phosphorylation by fluoxetine and iprindole.

Silver PJ, Sigg EB, Moyer JA.

The effects of several antidepressant and antipsychotic agents on Ca2+-calmodulin-regulated myosin light chain phosphorylation were evaluated. At a concentration of 100 microM, the antidepressant agents buproprion, mianserin and maprotiline were ineffective; zimelidine, desipramine and imipramine produced 40-50% inhibition; and iprindole and fluoxetine produced 75-90% inhibition. The efficacies of iprindole and fluoxetine were similar to the phenothiazine antipsychotics chlorpromazine and trifluoperazine. Clozapine, an atypical antipsychotic and the butyrophenone haloperidol were relatively ineffective as myosin light chain phosphorylation inhibitors. IC50 values of the most effective agents were: trifluoperazine 16 microM, fluoxetine 28 microM, chlorpromazine and iprindole 56 microM. As with trifluoperazine, inhibition of myosin phosphorylation by iprindole was completely attenuated in the presence of exogenous calmodulin. However, a significant component (30%) of the inhibitory effect of fluoxetine was not reversible with calmodulin. These results show that some antidepressant agents, most notably iprindole and fluoxetine, are capable of antagonizing a calmodulin-regulated protein kinase through calmodulin inhibition; and in the case of fluoxetine, through an additional calmodulin-independent mechanism.

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Pharmacol Biochem Behav. 1986 Feb;24(2):199-204.
The effects of fluoxetine and zimeldine on the behavior of olfactory bulbectomized rats.

Joly D, Sanger DJ.

Previous work has shown that subchronic administration of antidepressant drugs can reverse the behavioral and physiological changes produced by removal of the olfactory bulbs of rats. It has also been reported that acute administration of drugs believed to enhance serotonergic transmission can improve passive avoidance performance in bulbectomized rats. In order to follow up this observation the effects of the serotonin reuptake inhibitor, fluoxetine, were studied in bulbectomized and control rats. Fluoxetine produced a dose-related improvement in the passive avoidance behavior of bulbectomized rats in a step-down task and in a Y-maze. The effect of fluoxetine on step-down avoidance was blocked by metergoline and was also shown by zimeldine, another inhibitor of serotonin reuptake. However, in tests of active avoidance responding in a shuttle box and exploratory locomotion, fluoxetine produced similar disruptions of behavior in both bulbectomized and control animals. Thus, the effects of fluoxetine on the behavior of bulbectomized rats are dependent upon the behavioral test.

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Life Sci. 1985 Jun 17;36(24):2317-23.
Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors.

Hynes MD, Lochner MA, Bemis KG, Hymson DL.

The analgesic effect of morphine in the rat tail jerk assay was enhanced by the serotonin uptake inhibitor, fluoxetine. Tail jerk latency was not affected by fluoxetine alone. Morphine's affinity for opioid receptors labeled in vitro with 3H-naloxone or 3H-D-Ala2-D-Leu5-enkephalin was not altered by fluoxetine, which has no affinity for these sites at concentrations as high as 1000 nM. In rats trained to discriminate morphine from saline, fluoxetine at doses of 5 or 10 mg/kg were recognized as saline. Increasing the fluoxetine dose to 20 mg/kg did not result in generalization to either saline or morphine. The dose response curve for morphine generalization was not significantly altered by fluoxetine doses of 5 or 10 mg/kg. Those rats treated with the combination of morphine and 20 mg/kg of fluoxetine did not exhibit saline or morphine appropriate responding. Fluoxetine potentiates the analgesic properties of morphine without enhancing its affinity for opioid receptors or its discriminative stimulus properties.

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J Neural Transm. 1985;64(3-4):251-69.
Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors.

Wong DT, Reid LR, Bymaster FP, Threlkeld PG.

Fluoxetine administration to rats at a dose of 10 mg/kg i.p. daily up to 12 or 24 days failed to change the concentration-dependent binding of [3H]WB4101, [3H]clonidine and [3H]dihydroalprenolol to alpha 1-, alpha 2- and beta-adrenergic receptors, respectively; [3H]quinuclidinyl benzilate to muscarinic receptors; [3H]pyrilamine to histamine H1 receptors and [3H]naloxone to opiate receptors. Persistent and significant decreases in receptor number (Bmax value) without changes in the dissociation constant (KD value) of [3H]5-HT binding in cortical membranes were observed upon chronic treatment with fluoxetine administered either by intraperitoneal injection or incorporation in the diet. A detectable reduction of 5-HT1 receptor number occurred after once-daily injections of fluoxetine at 10 mg/kg i.p. within 49 hours. After pretreatment for 3 days with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, followed by repeated administration of fluoxetine, 5-HT1 receptor numbers were higher than those of normal rats, suggesting a dependence on synaptic concentration of 5-HT for fluoxetine to affect a receptor down-regulation. These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of 5-HT1 receptors in the cerebral cortex of rat brain.

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Brain Behav Immun. 2002 Apr;16(2):87-103.
Role of central 5-HT(2) receptors in fluoxetine-induced decreases in T lymphocyte activity.

Pellegrino TC, Bayer BM.

Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC 20007, USA.

Previous studies have demonstrated that fluoxetine administration decreases mitogen-induced T lymphocyte proliferation. The present studies were carried out to determine which receptor subtype(s) was involved and whether these effects on lymphocyte responses were centrally or peripherally mediated. Two hours following administration of the 5-HT(1A) agonist 8-OH-DPAT (1 mg/kg), there was no change in lymphocyte proliferation responses, whereas the 5-HT(2) agonist DOI (2.5 mg/kg) significantly decreased (80%) proliferation. Similarly, pretreatment with the 5-HT(2) antagonists ritanserin (5 mg/kg, 30 min) or ketanserin (5 mg/kg, 1 h) was found to completely antagonize the effects of fluoxetine on lymphocyte proliferation. Consistent with central 5-HT(2) receptor involvement, microinjection of DOI (50 microg) resulted in a decrease in lymphocyte proliferation similar to that observed following systemic administration. Furthermore, central administration of ketanserin (20 microg) prevented the suppressive effects of systemic fluoxetine. Collectively, these results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration was due to indirect effects of fluoxetine following the activation of central 5-HT(2) receptors. Copyright 2001 Elsevier Science (USA).

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