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

Psychopharmacology (Berl). 2015 Sep;232(18):3431-41. doi: 10.1007/s00213-015-3995-x. Epub 2015 Jul 5.

Abstract

Rationale: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking
  • Alcoholism / drug therapy
  • Animals
  • Autoradiography
  • Behavior, Animal / drug effects*
  • Central Nervous System Depressants / administration & dosage*
  • Cross-Over Studies
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Ethanol / administration & dosage*
  • Indans / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naltrexone / pharmacology*
  • Narcotic Antagonists / pharmacology*
  • Radiopharmaceuticals
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Self Administration
  • Triazoles / pharmacology*
  • Tritium

Substances

  • Central Nervous System Depressants
  • Indans
  • N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine
  • Narcotic Antagonists
  • Radiopharmaceuticals
  • Receptors, Opioid, mu
  • Triazoles
  • Tritium
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Ethanol
  • Naltrexone