Abstract
Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1−1−3 mg/kg) or GSK1521498 (0.1–1–3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.
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Acknowledgements
This study was funded by Medical Research Council Programme Grant (no. G1002231) and by GlaxoSmithKline (GSK) that has a commercial interest in GSK1521498. The production of the P/NP and HAD rats was funded by the R24 Alcohol Research Resource Award grant (R24 AA015512) from NIAAA. Charles R Goodlett was funded by a grant from the IUPUI International Development Fund that supported his sabbatical leave at the University of Cambridge. Maria Pilar Garcia-Pardo was funded by Val+id para investigadores en formación (Conselleria de educacion, Generalitat Valenciana) that also supported her stay at the University of Cambridge (January–April 2014) as a visiting student. With this paper we would like to commemorate Daina Economidou who died in December 2012 after a heroic fight against lung cancer. The best way to remember her is to share with the scientific community her dedication and enthusiastic contribution to science through the data collected until a few months before her death, including the data in Figure 1. We thank Dr Larry Lumeng, Dr Richard Bell, and Rebecca Jane Smith at the Indiana University School of Medicine for facilitating the provision of the selected lines of rats; Dr Adam Mar for writing the program to analyze the EPM data; Dr Yolanda Peña-Oliver for analyzing the EPM data; Jing Xia for analyzing the blood samples; Sam Miller for excellent statistical advice; and Kristin Patterson and Ramprakash Govindarajan for providing the GSK1521498 solutions.
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Giuliano, C., Goodlett, C., Economidou, D. et al. The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking. Neuropsychopharmacol 40, 2981–2992 (2015). https://doi.org/10.1038/npp.2015.152
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DOI: https://doi.org/10.1038/npp.2015.152
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