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

Ripley TL, Sanchez-Roige S, Bullmore ET, Mugnaini M, Maltby K, Miller SR, Wille DR, Nathan P, Stephens DN - Psychopharmacology (Berl.) (2015)

Bottom Line: 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.Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.

View Article: PubMed Central - PubMed

Affiliation: School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of GSK1521498 and LiCl in supporting a conditioned taste aversion for a sucrose solution in ethanol naive C57BL/6J mice. a Sucrose consumed (ml) on the conditioning day (pre) and test day (post). b Water consumption (ml) on the specificity test day
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Fig6: Effect of GSK1521498 and LiCl in supporting a conditioned taste aversion for a sucrose solution in ethanol naive C57BL/6J mice. a Sucrose consumed (ml) on the conditioning day (pre) and test day (post). b Water consumption (ml) on the specificity test day

Mentions: A conditioned taste aversion to LiCl was seen as a significant decrease in sucrose consumption on the test day compared with the conditioning day (t7 = 4.24, p < 0.005; Fig. 6).Fig. 6


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

Ripley TL, Sanchez-Roige S, Bullmore ET, Mugnaini M, Maltby K, Miller SR, Wille DR, Nathan P, Stephens DN - Psychopharmacology (Berl.) (2015)

Effect of GSK1521498 and LiCl in supporting a conditioned taste aversion for a sucrose solution in ethanol naive C57BL/6J mice. a Sucrose consumed (ml) on the conditioning day (pre) and test day (post). b Water consumption (ml) on the specificity test day
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537503&req=5

Fig6: Effect of GSK1521498 and LiCl in supporting a conditioned taste aversion for a sucrose solution in ethanol naive C57BL/6J mice. a Sucrose consumed (ml) on the conditioning day (pre) and test day (post). b Water consumption (ml) on the specificity test day
Mentions: A conditioned taste aversion to LiCl was seen as a significant decrease in sucrose consumption on the test day compared with the conditioning day (t7 = 4.24, p < 0.005; Fig. 6).Fig. 6

Bottom Line: 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.Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.

View Article: PubMed Central - PubMed

Affiliation: School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, UK.

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.

No MeSH data available.


Related in: MedlinePlus