New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models

Majeed, Zana R.; Ritter, Kyle; Robinson, Jonathan L.; Blümich, Sandra L.E.; Brǎiloiu, Eugen; Cooper, Robin L.

doi:10.1016/j.cbpc.2015.07.010

Cited by 11 publications

(11 citation statements)

References 64 publications

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“…The polymorphism of CYP2C19 has an impact on the efficacy of drugs, which led to drug interactions or side effects [14,15]. Patients carrying metabolic enhanced CYP2C19 alleles can metabolize drugs quicker than those carrying the wild-type; this will not lead to desired results because of the rapid decline of plasma concentrations [27].…”

Section: Discussionmentioning

confidence: 99%

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Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro

Fang

He²,

Han³

et al. 2017

Pharmacology

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Aims: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro. Methods: The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min. By using ultra-high performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters K_m, V_max, and intrinsic clearance (V_max/K_m) of norfluoxetine were determined. Results: Among the CYP2C19 variants tested, T130M showed similar intrinsic clearance (V_max/K_m) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 9.56 to 77.77%). In addition, CYP2C19*3 and *35FS could not be detected because they have no detectable enzyme activity. Conclusion: In China, the assessment of CYP2C19 variants in vitro offers valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.

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Section: Discussionmentioning

confidence: 99%

“…Several individuals died because they were acutely intoxicated with fluoxetine. The reduced metabolism caused the accumulation of fluoxetine in the body and resulted in the death of these patients [14,15]. …”

Section: Introductionmentioning

confidence: 99%

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro

Fang

He²,

Han³

et al. 2017

Pharmacology

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“…The affinity of fluoxetine for Drosophila SERT was previously determined to be lower ( K i = 72 nM) than for mammals [ 47 ]. High concentrations of fluoxetine are toxic to larval and adult Drosophila [ 62 ] so we stuck to a 10 mM concentration for this study.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has demonstrated that application of 100 μ M of fluoxetine while stimulating channelrhodopsin-2 expressing 5-HT neurons results in blockage of 5-HT reuptake in Drosophila larval ventral nerve cord [ 67 ]. It has been shown that fluoxetine can block ion channels [ 68 , 69 ]; therefore, the interpretation of these results is difficult since we have to ensure that the observed effect of fluoxetine is due to the dysregulation of 5-HT level and no other possible nonselective side effects (see [ 62 ]). This opens new avenues for the future studies on the mechanism of action of fluoxetine in altering the development in neural circuitry.…”

Section: Discussionmentioning

confidence: 99%

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology inDrosophila melanogaster

et al. 2016

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Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs) in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity.

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“…Interestingly, inhibitory α 2 adrenergic heteroreceptors also exist in serotonergic terminals [68], while data supporting the presence of 5-HT heteroreceptors regulating the release of noradrenaline in noradrenergic terminals are lacking [69]. Although the possibility exists that “in vivo” fluoxetine and reboxetine could also target other membrane targets [70], the distribution of the auto- and the heteroreceptors in noradrenergic and serotonergic appeared well consistent with the functional adaptations observed in hippocampal synaptosomes from rat administered acutely with the two antidepressants. Actually, the “in vivo” activation of both the α 2 autoreceptors and the α 2 heteroreceptors that would follow the acute administration of reboxetine could account for the reduced exocytosis of both noradrenaline and serotonin, while, based on the data so far available in the literature, serotonin-induced activation of serotonergic receptors only occurs at serotonergic terminals, since noradrenergic terminals do not possess serotonin release-regulating heteroreceptors.…”

Section: Acute “In Vivo” Drug Administration Elicits Persistent Prmentioning

confidence: 99%

Acute Functional Adaptations in Isolated Presynaptic Terminals Unveil Synaptosomal Learning and Memory

Pittaluga

2019

IJMS

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Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming whether the activation of presynaptic receptors/enzymes can modulate this event. In the last two decades, important progress in the field came from the observations that synaptosomes retain changes elicited by both “in vivo” and “in vitro” acute chemical stimulation. The novelty of these studies is the finding that these adaptations persist beyond the washout of the triggering drug, emerging subsequently as functional modifications of synaptosomal performances, including release efficiency. These findings support the conclusion that synaptosomes are plastic entities that respond dynamically to ambient stimulation, but also that they “learn and memorize” the functional adaptation triggered by acute exposure to chemical agents. This work aims at reviewing the results so far available concerning this form of synaptosomal learning, also highlighting the role of these acute chemical adaptations in pathological conditions.

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New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models

Cited by 11 publications

References 64 publications

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology inDrosophila melanogaster

Acute Functional Adaptations in Isolated Presynaptic Terminals Unveil Synaptosomal Learning and Memory

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