The novel µ-opioid receptor antagonist GSK1521498 decreases both alcohol seeking and drinking: evidence from a new preclinical model of alcohol seeking
Goodlett, Charles R
García-Pardo, Maria P
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Giuliano, C., Goodlett, C. R., Economidou, D., García-Pardo, M. P., Belin, D., Robbins, T., Bullmore, E., & et al. (2015). The novel µ-opioid receptor antagonist GSK1521498 decreases both alcohol seeking and drinking: evidence from a new preclinical model of alcohol seeking. Neuropsychopharmacology, 40 2981-2992. https://doi.org/10.1038/npp.2015.152
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 CS 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. Re-derived alcohol-preferring, alcohol-nonpreferring and high alcohol-drinking replicate 1 lines of rats (Indiana University, USA) 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 pre-treatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) prior to 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.
Addiction, Alcohol seeking, Alcohol-preferring rats, Conditioned stimulus, Naltrexone, µ-opioid receptor antagonist
The present study was funded by Medical Research Council Programme Grant (no. G1002231) and by GlaxoSmithKline (GSK), which has a commercial interest in GSK1521498. Charles R. Goodlett was funded by a grant from the IUPUI International Development Fund, which 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), which also supported her stay at the University of Cambridge (January-April 2014) as a Visiting Student.
MEDICAL RESEARCH COUNCIL (G0001354)
External DOI: https://doi.org/10.1038/npp.2015.152
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248587