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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

Effects of GSK1521498 and naltrexone on ethanol consumption in the DID procedure when the doses were matched for receptor occupancy. a MOPr occupancy in the striatum at different doses of drug. Over the dose ranges used, naltrexone showed greater occupancy than GSK1521498. b Ethanol consumption in the DID procedure at doses of drug that produced a 70–75 % occupancy. When the dose of the drug was matched for occupancy, animals treated with GSK1521498 consumed significantly less ethanol than animals treated with naltrexone (*p < 0.001). Bars indicate SEM. c Fold decrease in ethanol consumption vs 0 mg/kg dose (baseline-adjusted). Bars indicate 95 % confidence intervals
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Fig4: Effects of GSK1521498 and naltrexone on ethanol consumption in the DID procedure when the doses were matched for receptor occupancy. a MOPr occupancy in the striatum at different doses of drug. Over the dose ranges used, naltrexone showed greater occupancy than GSK1521498. b Ethanol consumption in the DID procedure at doses of drug that produced a 70–75 % occupancy. When the dose of the drug was matched for occupancy, animals treated with GSK1521498 consumed significantly less ethanol than animals treated with naltrexone (*p < 0.001). Bars indicate SEM. c Fold decrease in ethanol consumption vs 0 mg/kg dose (baseline-adjusted). Bars indicate 95 % confidence intervals

Mentions: In order to compare intrinsic efficacy of the two drugs, receptor occupancy was expressed as a function of drug dose for each drug. Figure 4a shows that naltrexone gave rise to greater receptor occupancies than GSK1521498 over the dose ranges and routes of administration used, suggesting a greater potency. In order to compare the relative efficacies of the two substances, we chose to compare drug effects at doses of each drug giving rise to similar receptor occupancy in the range 70–75 %. For naltrexone, this degree of occupancy corresponded to a dose of 0.1 mg/kg, s.c., whereas an i.p. dose of 3 mg/kg of GSK1521498 gave rise to the same occupancy of striatal receptors (t6 = 0.34, p = 0.749). Figure 4b shows that at this receptor occupancy, GSK1521498 reduced ethanol intake to a greater extent than naltrexone. Figure 4c presents these data as fold change from baseline (t145 = 3.73, p < 0.001).Fig. 4


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)

Effects of GSK1521498 and naltrexone on ethanol consumption in the DID procedure when the doses were matched for receptor occupancy. a MOPr occupancy in the striatum at different doses of drug. Over the dose ranges used, naltrexone showed greater occupancy than GSK1521498. b Ethanol consumption in the DID procedure at doses of drug that produced a 70–75 % occupancy. When the dose of the drug was matched for occupancy, animals treated with GSK1521498 consumed significantly less ethanol than animals treated with naltrexone (*p < 0.001). Bars indicate SEM. c Fold decrease in ethanol consumption vs 0 mg/kg dose (baseline-adjusted). Bars indicate 95 % confidence intervals
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: Effects of GSK1521498 and naltrexone on ethanol consumption in the DID procedure when the doses were matched for receptor occupancy. a MOPr occupancy in the striatum at different doses of drug. Over the dose ranges used, naltrexone showed greater occupancy than GSK1521498. b Ethanol consumption in the DID procedure at doses of drug that produced a 70–75 % occupancy. When the dose of the drug was matched for occupancy, animals treated with GSK1521498 consumed significantly less ethanol than animals treated with naltrexone (*p < 0.001). Bars indicate SEM. c Fold decrease in ethanol consumption vs 0 mg/kg dose (baseline-adjusted). Bars indicate 95 % confidence intervals
Mentions: In order to compare intrinsic efficacy of the two drugs, receptor occupancy was expressed as a function of drug dose for each drug. Figure 4a shows that naltrexone gave rise to greater receptor occupancies than GSK1521498 over the dose ranges and routes of administration used, suggesting a greater potency. In order to compare the relative efficacies of the two substances, we chose to compare drug effects at doses of each drug giving rise to similar receptor occupancy in the range 70–75 %. For naltrexone, this degree of occupancy corresponded to a dose of 0.1 mg/kg, s.c., whereas an i.p. dose of 3 mg/kg of GSK1521498 gave rise to the same occupancy of striatal receptors (t6 = 0.34, p = 0.749). Figure 4b shows that at this receptor occupancy, GSK1521498 reduced ethanol intake to a greater extent than naltrexone. Figure 4c presents these data as fold change from baseline (t145 = 3.73, p < 0.001).Fig. 4

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