title: The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking.
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.
authors.affiliation: Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giuliano
authors.affiliation: Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Goodlett
authors.affiliation: Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Daina
authors.initials: D
authors.lastname: Economidou
authors.affiliation: Unit of Research Psychobiology of Drug Dependence, Department of Psychobiology, School of Psychology, University of Valencia, Valencia, Spain.
authors.forename: Maria P
authors.initials: MP
authors.lastname: García-Pardo
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-7383-372X
authors.initials: D
authors.lastname: Belin
authors.affiliation: Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.|Department of Psychiatry, University of Cambridge, Cambridge, UK.|Clinical Unit Cambridge and Academic DPU, GlaxoSmithKline R&D, Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
authors.affiliation: Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Everitt
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D000067401:Blood Alcohol Content; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012054:Reinforcement, Psychology; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000427:Alcohol Deterrents; D000067401:Blood Alcohol Content; D007189:Indans; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D014230:Triazoles; D009271:Naltrexone