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Ethanol as a Prodrug: Brain Metabolism of Ethanol Mediates its Reinforcing Effects

Authors

  • Eduardo Karahanian,

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    • Contributed equally to this work.

  • María Elena Quintanilla,

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    • Contributed equally to this work.

  • Lutske Tampier,

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    • Contributed equally to this work.

  • Mario Rivera-Meza,

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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  • Diego Bustamante,

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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  • Víctor Gonzalez-Lira,

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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  • Paola Morales,

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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  • Mario Herrera-Marschitz,

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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  • Yedy Israel

    1. From the Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; Program of Molecular and Clinical Pharmacology (MEQ, LT, MRM, DB, VGL, PM, MHM, YI), Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (MRM, YI), Faculty of Chemical and Pharmaceutical Sciences and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; and Department of Pathology, Anatomy and Cell Biology (YI), Thomas Jefferson University, Philadelphia, Pennsylvania.
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Reprint requests: Yedy Israel, Laboratory of Gene Therapy, University of Chile, Sergio Livingstone 1007, Independencia, Santiago, Chile; Tel.: +11 562 978 2943; Fax: +11 562 737 7291; E-mail: yisrael@uchile.cl or mh-marschitz@med.uchile.cl

Abstract

Background:  While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis.

Methods:  The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water.

Results:  Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (−94%p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption.

Conclusions:  The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.

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