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Paroxetine suppresses recombinant human P2X7 responses

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Abstract

P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit anti-depressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC50 of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC50 of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14+ monocytes was suppressed with trifluoperazine and paroxetine.

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Abbreviations

SSRI:

Selective serotonin reuptake inhibitor

IL-1β:

Interleukin 1 beta

LPS:

Lipopolysaccharide

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Acknowledgments

We thank Dr Ronald Sluyter (University of Wollongong) and Dr Suzanne Rogers (RMIT University, Melbourne) for helpful discussions and Ms Griselda Loza-Diaz (Sydney Medical School Nepean, University of Sydney) for assistance with venipuncture. This work was supported by the National Health and Medical Research Council, Australia (Grant ID 632687 to LS).

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Authors and Affiliations

  1. Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Level 5 South Block, Derby Street, Penrith, NSW, 2750, Australia

    Phuong Dao-Ung, Kristen K. Skarratt, Stephen J. Fuller & Leanne Stokes

  2. School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK

    Leanne Stokes

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  1. Phuong Dao-Ung
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  2. Kristen K. Skarratt
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  3. Stephen J. Fuller
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  4. Leanne Stokes
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Correspondence to Leanne Stokes.

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Dao-Ung, P., Skarratt, K.K., Fuller, S.J. et al. Paroxetine suppresses recombinant human P2X7 responses. Purinergic Signalling 11, 481–490 (2015). https://doi.org/10.1007/s11302-015-9467-2

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  • DOI: https://doi.org/10.1007/s11302-015-9467-2

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