The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice

Abstract

RationaleUsing the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.ObjectiveWe test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.MethodsThirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding.ResultsBoth GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70–75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection.ConclusionsBoth opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3995-x) contains supplementary material, which is available to authorized users.

Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype

“…GSK1521498 is a novel μ-opioid receptor antagonist ( Ignar et al , 2011 ; Kelly et al , 2015 ) with some inverse agonist properties that is being investigated for the treatment of disorders of compulsive consumption of food, alcohol, and drugs. GSK1521498 has been differentiated from NTX in a series of human, animal, and cellular models in terms of its opioid receptor pharmacology, its pharmacokinetics, and its greater pharmacodynamic efficacy on functional magnetic resonance imaging (fMRI) activation by fruit juice, on consumption of food and alcohol, and on behavioral models of drug seeking behavior for heroin, cocaine, and alcohol ( Ignar et al , 2011 ; Rabiner et al , 2011 ; Kelly et al , 2015 ; Giuliano et al , 2012 , 2013 , 2015 ; Ripley et al , 2015 ). In humans, GSK1521498 reduced the pleasurable response to high-fat/high-sugar food samples ( Nathan et al , 2012 ; Ziauddeen et al , 2013a ), food intake ( Ziauddeen et al , 2013a ), attentional bias to foods ( Chamberlain et al , 2012 ), and fMRI activation by food images ( Cambridge et al , 2012 ).…”

The Role of NFkB in Drug Addiction: Beyond Inflammation

“…For alcohol, microinjections of the MOR agonist (D-Ala2, N-MePhe4, Gly-ol)-enkephalin into the nucleus accumbens shell increases alcohol intake and enhances cueinduced reinstatement (Richard and Fields, 2016). Conversely, MOR antagonists decrease alcohol consumption in rats (Stromberg et al, 1998;Ripley et al, 2015). Stimulation of β-endorphin release and activation of the MOR is thought to be a major mechanism by which alcohol has its rewarding properties.…”

Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats

“…Opioid receptor-mediated mechanisms have been shown to reduce alcohol drinking, craving for alcohol and established CS-controlled alcohol seeking (Vengeliene et al, 2008); moreover μ-opioid receptors in the prefrontal context have been implicated in compulsive eating (Blasio et al, 2014). We have therefore investigated μ-opioid mechanisms in compulsive alcohol seeking in our newly established procedure using the most selective and well-characterized, in vitro and in vivo (Giuliano et al, 2012(Giuliano et al, , 2013Ignar et al, 2011;Kelly et al, 2015;Ripley et al, 2015;Ziauddeen et al, 2013Ziauddeen et al, , 2016, μ-opioid receptor antagonist GSK1521498. We have shown previously that this compound is more effective than naltrexone in reducing cue-controlled alcohol seeking and also alcohol drinking .…”