Limits...
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

Ethanol consumption following administration of GSK1521498 or naltrexone when the data were combined across phases 1 and 2 of the study: both GSK1521498 and naltrexone produced a significant decrease in ethanol consumption, but this effect was less pronounced following naltrexone administration. Baseline refers to consumption on day prior to respective injection day. Data points for the 0 mg/kg dose have been offset to allow the reader to interpret the error bars.*p < 0.05, significantly different from vehicle. Bars indicate SEM. The same data, plotted as percentage change from baseline, are shown in Supplementary Fig. 1
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4537503&req=5

Fig3: Ethanol consumption following administration of GSK1521498 or naltrexone when the data were combined across phases 1 and 2 of the study: both GSK1521498 and naltrexone produced a significant decrease in ethanol consumption, but this effect was less pronounced following naltrexone administration. Baseline refers to consumption on day prior to respective injection day. Data points for the 0 mg/kg dose have been offset to allow the reader to interpret the error bars.*p < 0.05, significantly different from vehicle. Bars indicate SEM. The same data, plotted as percentage change from baseline, are shown in Supplementary Fig. 1

Mentions: Figure 3 shows average weekly ethanol consumption during DID on both the day prior to drug administration (baseline) and on drug administration days. Table 1 presents the fold changes in ethanol consumption (compared to non-injection days and placebo sessions). The injection procedure produced a small reduction in drinking when compared to non-injection baseline days, but there was no difference among the groups, suggesting that although the injection procedure reduced alcohol consumption, there was no evidence that the order of dosing had effects. There was also a significant difference in consumption between phases (F1,125 = 34.7, p < 0.01), with greater consumption in phase 1. However, there were no significant interactions between phase and other effects of interest, and a sensitivity analysis restricted to only phase 1 data gave similar estimates to those in Table 1, implying that the fold reductions in drinking were consistent irrespective of the baseline drinking level within each phase.Fig. 3


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)

Ethanol consumption following administration of GSK1521498 or naltrexone when the data were combined across phases 1 and 2 of the study: both GSK1521498 and naltrexone produced a significant decrease in ethanol consumption, but this effect was less pronounced following naltrexone administration. Baseline refers to consumption on day prior to respective injection day. Data points for the 0 mg/kg dose have been offset to allow the reader to interpret the error bars.*p < 0.05, significantly different from vehicle. Bars indicate SEM. The same data, plotted as percentage change from baseline, are shown in Supplementary Fig. 1
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Ethanol consumption following administration of GSK1521498 or naltrexone when the data were combined across phases 1 and 2 of the study: both GSK1521498 and naltrexone produced a significant decrease in ethanol consumption, but this effect was less pronounced following naltrexone administration. Baseline refers to consumption on day prior to respective injection day. Data points for the 0 mg/kg dose have been offset to allow the reader to interpret the error bars.*p < 0.05, significantly different from vehicle. Bars indicate SEM. The same data, plotted as percentage change from baseline, are shown in Supplementary Fig. 1
Mentions: Figure 3 shows average weekly ethanol consumption during DID on both the day prior to drug administration (baseline) and on drug administration days. Table 1 presents the fold changes in ethanol consumption (compared to non-injection days and placebo sessions). The injection procedure produced a small reduction in drinking when compared to non-injection baseline days, but there was no difference among the groups, suggesting that although the injection procedure reduced alcohol consumption, there was no evidence that the order of dosing had effects. There was also a significant difference in consumption between phases (F1,125 = 34.7, p < 0.01), with greater consumption in phase 1. However, there were no significant interactions between phase and other effects of interest, and a sensitivity analysis restricted to only phase 1 data gave similar estimates to those in Table 1, implying that the fold reductions in drinking were consistent irrespective of the baseline drinking level within each phase.Fig. 3

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