Rationale Using the drinking-in-the-dark (DID) model, we\ncompared the effects of a novel mu-opioid receptor antagonist,\nGSK1521498, with naltrexone, a licensed treatment of alcohol\ndependence, on ethanol consumption in mice.\nObjective We test the ability of GSK1521498 to reduce alcohol\nconsumption and compare its intrinsic efficacy to that of\nnaltrexone by comparing the two drugs at doses matched for\nequivalent receptor occupancy.\nMethods Thirty-six C57BL/6J mice were tested in a DID procedure.\nIn 2-day cycles, animals experienced one baseline,\ninjection-free session, and one test session when they received\ntwo injections, one of test drug and one placebo. All animals\nreceived GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min\npre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c.\n10 min pre-treatment) in a cross-over design. Receptor\noccupancies following the same doses were determined\nex vivo in separate groups by autoradiography, using\n[3H]DAMGO. Binding in the region of interest was measured\nintegrally by computer-assisted microdensitometry and\ncorrected for non-specific binding.\nResults Both GSK1521498 and naltrexone dose-dependently\ndecreased ethanol consumption. When drug doses were\nmatched for 70ââ?¬â??75 % receptor occupancy, GSK1521498\n3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol\nconsumption than naltrexone 0.1 mg/kg, s.c. Both\nGSK1521498 and naltrexone significantly reduced sucrose\nconsumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test\nof conditioned taste aversion, GSK1521498 (3 mg/kg) reduced\nsucrose consumption 24 h following exposure to a conditioning\ninjection.\nConclusions Both opioid receptor antagonists reduced alcohol\nconsumption but GK1521498 has higher intrinsic efficacy\nthan naltrexone.
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