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Reward and Relapse: Complete Gene-Induced Dissociation in an Animal Model of Alcohol Dependence

Authors

  • María E. Quintanilla,

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

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

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

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

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

    1. From the Program of Molecular and Clinical Pharmacology (MEQ, LT, MR-M, MH-M, YI), Faculty of Medicine, Institute of Biomedical Sciences, Santiago, Chile; Department of Pharmacological and Toxicological Chemistry (YI), Faculty of Chemical and Pharmaceutical Sciences, and Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile; Center of Biomedical Research (EK), Faculty of Medicine, Universidad Diego Portales, Santiago, Chile; and Department of Pathology (YI), Anatomy and Cell Biology, 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

Abstract

Background:  In animal models of continuous alcohol self-administration, in which physical dependence does not constitute the major factor of ethanol intake, 2 factors likely contribute to the perpetuation of alcohol self-administration: (i) the rewarding effects of ethanol and (ii) the contextual conditioning cues that exist along with the process of self-administration. Present studies are aimed at understanding the relative contribution of these factors on the perpetuation of heavy alcohol self-administration, as an indication of relapse.

Methods:  Wistar-derived UChB high ethanol drinker rats were allowed access to 10% ethanol and water on a 24-hour basis. In initial studies, an anticatalase shRNA gene-coding lentiviral vector aimed at inhibiting acetaldehyde generation was administered into the ventral tegmental area (VTA) of the animals prior to ethanol access. In subsequent studies, the lentiviral vector was administered to animals, which had consumed ethanol on a 24-hour basis, or a 1-hour basis, after the animals had reached high levels of ethanol intake for 60 to 80 days. In final studies, quinine (0.01%) was added to the ethanol solution to alter the conditioning taste/smell cues of alcohol that animals had chronically ingested.

Results:  Data indicate that the administration of an anticatalase vector into the VTA of naïve animals blocked reward and alcohol self-administration, while it was, nevertheless, inactive in inhibiting alcohol self-administration in rats that had been conditioned to ingest ethanol for over 2 months. The lack of inhibitory effect of the anticatalase vector on ethanol intake in animals that had chronically self-administered ethanol was fully reversed when the contextual conditioning cues of the alcohol solution were changed.

Conclusions:  Data highlight the importance of conditioning factors in relapse and suggest that only abolishing or blunting it, along with long-lasting pharmacological treatment to reduce ethanol reward, may have protracted effects in reducing alcohol self-administration.

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