Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors

Wong, David T.; Bymaster, Frank P.; Reid, Leroy R.; Threlkeld, Penny G.

doi:10.1016/0006-2952(83)90284-8

Cited by 168 publications

(59 citation statements)

References 31 publications

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“…Although both fluoxetine and sertraline presumably exert antidepressant effects by increasing brain 5-HT levels as a result of blocking serotonin reuptake (Heym and Koe 1988;Koe et al 1983;Wong et al 1983 by fluoxetine were also seen in hypothalamus, another brain region of relevance in depression, as reported by previous studies Fuller 1992, 1997). The olanzapine and fluoxetine combination treatment greatly increased both [DA] ex and [NE] ex , even at 4 hours after the initial drug treatment.…”

Section: Discussionmentioning

confidence: 78%

Synergistic Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine on Norepinephrine and Dopamine Release in Rat Prefrontal Cortex

Zhang

Perry

Wong

et al. 2000

Neuropsychopharmacology

191

136

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Section: Discussionmentioning

confidence: 78%

Synergistic Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine on Norepinephrine and Dopamine Release in Rat Prefrontal Cortex

Zhang

Perry

Wong

et al. 2000

Neuropsychopharmacology

191

136

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“…The two enantiomers of norfluoxetine are similar to fluoxetine (Wong et al 1983) and its two enantiomers (Wong et al 1985), and have little affinity for receptors of neurotransmitters, including 5-HT, NE, DA, acetyl choline, and histamine. The relatively low affinity of the norfluoxetine enantiomers for receptors of acetyl choline (muscarinic class) and histamine is consistent with the low incidence of anticholinergic and anti histaminergic side-effect profIles of fluoxetine and norfluoxetine (Feighner 1983;Beasley et al 1990).…”

Section: Discussionmentioning

confidence: 99%

Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Wong

Bymaster

Reid

et al. 1993

Neuropsychopharmacol

Self Cite

104

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lit fiuoxetine, the N-demethylated metabolite ."" uoxetine exists in R-and S-enantiomeric fonns. S-Norfluoxetine inhibited serotonin (5-HT) uptake and I'Hlptlroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas l-norfluoxetine was 22 and 20 times, respectively, less pDltnt. R-and S-Norfluoxetine were less potent than the tlmSponding enantiomers of fluoxetine as inhibitors of WMpinephrine uptake and [3HJtomoxetine binding to WMpinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 "8!kg intraperitoneally, 4.7 mglkg subcutaneously, and lEY WORDS: Fluoxetine; Norfluoxetine; Enantiomers; Strotonin 5-HT; Uptake; Inhibitors Ruoxetine, a selective inhibitor of serotonin (5-hydroxy lIyptamine, 5-HT) uptake (Wong et aI., 1974(Wong et aI., , 1975, has been successfully developed as an antidepressant drug (Feighner 1983;Beasley et al. 1990). Fluoxetine is de ftIoped and is marketed as the racemate, i.e., the R (-) and 5 (+) enantiomers of equal amounts. Both enantiomers inhibit 5-HT uptake and effectively pro duce functional responses associated with an increased S-HT transmission. There are no major differences in potency between R-and S-fluoxetine, and their eudis IIic ratio is close to unity (Wong et al., 1985(Wong et al., , 1990 9 mglkg orally (7.3, 11.4 and 21.9 Jimollkg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mglkg intraperitoneally (48.6 Jimollkg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo. Robertson et aI. 1988). Enzymatic N-demethylation is an early step of fluoxetine metabolism, and the de methylated compound norfluoxetine (Fig. 1) is a major metabolite (Parli and Hicks 1974; Lemberger et aI. 1978;Beasley et al. 1990) in laboratory animals and in man. Norfluoxetine is also a potent and selective inhibitor of 5-HT uptake (Wong et aI. 1975; Horng and Wong 1976;Fuller et al. 1978). In the present communication, we report the pharmacologic pro&les of R-and S-norfluox etine, which have been recently synthesized in high enantiomeric purity. In contrast with the two enan tiomers of fluoxetine, however, we have found that S-norfluoxetine is over 20-fold more potent than the R enantiomer as an inhibitor of 5-HT uptake both in vitro and in vivo. MATERIALS AND METHODSMale Sprague-Dawley rats weighing between 100 and 150 g (Harlan Industries, Cumberland, IN) were housed in a room with a 12-hour dark/light cycle at 23°C, and

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“…The authors interpreted this as indicating that adding fluvoxamine modulates the effect of haloperidol on dopamine metabolism. Because, like other SSRIs, fluvoxamine does not block dopaminergic receptors, 40 inhibit MAO activity, 41 or directly affect dopamine turnover, 38,42,43 it is likely that, when combined with haloperidol, fluvoxamine modifies dopamine pathways indirectly, perhaps via the serotonergic system. 44 These effects appear to depend on chronic administration, given findings from acute studies of increased dopamine release in rat prefrontal cortex after 5-HT uptake inhibitors combined with haloperidol, an effect not produced by the individual drugs, [45][46][47][48] but no change in dopamine metabolism 49,50 in the striatum.…”

Section: Monoamine Systemsmentioning

confidence: 99%

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

et al. 2009

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Summary: Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRIantipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.

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Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors

Cited by 168 publications

References 31 publications

Synergistic Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine on Norepinephrine and Dopamine Release in Rat Prefrontal Cortex

Synergistic Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine on Norepinephrine and Dopamine Release in Rat Prefrontal Cortex

Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

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