title: The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.
abstract: BACKGROUND
  Using 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.
  
  
  OBJECTIVE
  We 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.
  
  
  METHODS
  Thirty-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.
  
  
  RESULTS
  Both 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.
  
  
  CONCLUSIONS
  Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.
authors.affiliation: School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
authors.forename: Tamzin L
authors.initials: TL
authors.lastname: Ripley
authors.forename: Sandra
authors.initials: S
authors.lastname: Sanchez-Roige
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
authors.forename: Manolo
authors.initials: M
authors.lastname: Mugnaini
authors.forename: Kay
authors.initials: K
authors.lastname: Maltby
authors.forename: Sam R
authors.initials: SR
authors.lastname: Miller
authors.forename: David R
authors.initials: DR
authors.lastname: Wille
authors.forename: Pradeep
authors.initials: P
authors.lastname: Nathan
authors.forename: David N
authors.initials: DN
authors.lastname: Stephens
mesh_terms: D000428:Alcohol Drinking; D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D018592:Cross-Over Studies; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D000431:Ethanol / Q000008:administration & dosage*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D012646:Self Administration; D014230:Triazoles / Q000494:pharmacology*; D014316:Tritium
chemical_list: D002492:Central Nervous System Depressants; 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; D019275:Radiopharmaceuticals; D017450:Receptors, Opioid, mu; D014230:Triazoles; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D000431:Ethanol; D009271:Naltrexone