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Contribution of P2X4 Receptors to Ethanol Intake in Male C57BL/6 Mice

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Abstract

P2X receptors (P2XRs) are a family of cation-permeable ligand-gated ion channels activated by synaptically released extracellular adenosine 5′-triphosphate. The P2X4 subtype is abundantly expressed in the central nervous system and is sensitive to low intoxicating ethanol concentrations. Genetic meta-analyses identified the p2rx4 gene as a candidate gene for innate alcohol intake and/or preference. The current study used mice lacking the p2rx4 gene (knockout, KO) and wildtype (WT) C57BL/6 controls to test the hypothesis that P2X4Rs contribute to ethanol intake. The early acquisition and early maintenance phases of ethanol intake were measured with three different drinking procedures. Further, we tested the effects of ivermectin (IVM), a drug previously shown to reduce ethanol’s effects on P2X4Rs and to reduce ethanol intake and preference, for its ability to differentially alter stable ethanol intake in KO and WT mice. Depending on the procedure and the concentration of the ethanol solution, ethanol intake was transiently increased in P2X4R KO versus WT mice during the acquisition of 24-h and limited access ethanol intake. IVM significantly reduced ethanol intake in P2X4R KO and WT mice, but the degree of reduction was 50 % less in the P2X4R KO mice. Western blot analysis identified significant changes in γ-aminobutyric acidA receptor α1 subunit expression in brain regions associated with the regulation of ethanol behaviors in P2X4R KO mice. These findings add to evidence that P2X4Rs contribute to ethanol intake and indicate that there is a complex interaction between P2X4Rs, ethanol, and other neurotransmitter receptor systems.

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Acknowledgments

This work was conducted as part of fulfillment of the requirements for the Ph.D. degree in Molecular Pharmacology and Toxicology, University of Southern California (L.R.W.). We thank Miriam Fine for technical assistance and USC Undergraduates (Ayee Azah, Christina Minh, Vanessa Fimreite, and Megan Won) and STAR students for laboratorial assistance. We also want to thank Chris Snelling at OHSU for conducting the analysis of BECRRs. This work was supported (in part or in full) by the National Institutes of Health (NIH), NIAAA, Grants F31AA018926 (L.R.W), KO-1-AA017243 (L.A.), AA016981 (D.A.F), AA03972 (R.L.A.), AA13992 and AA022448 (D.L.D); the American Foundation for Pharmaceutical Education (M.Y.); the Dept of Veterans Affairs (D.A.F); USC Undergraduate Provosts Fellowship (D.L.D. and V.F.), USC Summer Undergraduate Research Fund (D.L.D. and C.M.); and the USC School of Pharmacy (R.L.A and D.L.D).

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  1. Letisha R. Wyatt

    Present address: Legacy Research Institute, 1225 NE 2nd Avenue, Portland, OR, 97232, USA

Authors and Affiliations

  1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90033, USA

    Letisha R. Wyatt, Sheraz Khoja, Megan M. Yardley & Ronald L. Alkana

  2. Portland Alcohol Research Center, VA Medical Research, Oregon Health & Science University, Portland, OR, 97239, USA

    Deborah A. Finn

  3. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA

    Deborah A. Finn

  4. Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90033, USA

    Liana Asatryan & Daryl L. Davies

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  1. Letisha R. Wyatt
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Wyatt, L.R., Finn, D.A., Khoja, S. et al. Contribution of P2X4 Receptors to Ethanol Intake in Male C57BL/6 Mice. Neurochem Res 39, 1127–1139 (2014). https://doi.org/10.1007/s11064-014-1271-9

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