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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

Sucrose consumption following administration of GSK1521498 or naltrexone: there was a significant dose-dependent decrease in sucrose consumption with both GSK1521498 and naltrexone, which became significant at a dose of 1 mg/kg. *p < 0.05
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Fig5: Sucrose consumption following administration of GSK1521498 or naltrexone: there was a significant dose-dependent decrease in sucrose consumption with both GSK1521498 and naltrexone, which became significant at a dose of 1 mg/kg. *p < 0.05

Mentions: Specificity of the drug effect in reducing ethanol intake was tested using a 2 % sucrose solution in the sipper tubes. During the acquisition phase (first four sessions), animals were not injected. There was a significant increase in sucrose across this period (F3,75 = 20.01, p < 0.001), which stabilised after session 2 (consumption on day 4: 1.6 ± 0.2 ml). Figure 5 shows that both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg (main effect of GSK1521498: F2,52 = 8.05, p < 0.001; post hoc paired t test, 0 vs 1 mg/kg, t26 = 3.11, p < 0.01; main effect of naltrexone: F2,50 = 3.86, p < 0.05; post hoc paired t test, 0 vs 1 mg/kg, t25 = 2.28, p < 0.05).Fig. 5


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)

Sucrose consumption following administration of GSK1521498 or naltrexone: there was a significant dose-dependent decrease in sucrose consumption with both GSK1521498 and naltrexone, which became significant at a dose of 1 mg/kg. *p < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Sucrose consumption following administration of GSK1521498 or naltrexone: there was a significant dose-dependent decrease in sucrose consumption with both GSK1521498 and naltrexone, which became significant at a dose of 1 mg/kg. *p < 0.05
Mentions: Specificity of the drug effect in reducing ethanol intake was tested using a 2 % sucrose solution in the sipper tubes. During the acquisition phase (first four sessions), animals were not injected. There was a significant increase in sucrose across this period (F3,75 = 20.01, p < 0.001), which stabilised after session 2 (consumption on day 4: 1.6 ± 0.2 ml). Figure 5 shows that both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg (main effect of GSK1521498: F2,52 = 8.05, p < 0.001; post hoc paired t test, 0 vs 1 mg/kg, t26 = 3.11, p < 0.01; main effect of naltrexone: F2,50 = 3.86, p < 0.05; post hoc paired t test, 0 vs 1 mg/kg, t25 = 2.28, p < 0.05).Fig. 5

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