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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

Overview of the experimental protocol. The experiment was divided into four parts: a animals consumed ethanol in their home cage using the ethanol escalation model; b phase 1: following the establishment of baseline ethanol consumption using the DID method animals were divided into two groups with group A receiving GSK1521498 and group B receiving naltrexone as the test compound; c phase 2: following a 2-week wash-out period, DID was re-established and a cross-over design was employed such that group A received naltrexone and group B received GSK1521498 as the test compound; d compound specificity was tested using a 2 % sucrose DID protocol
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Fig1: Overview of the experimental protocol. The experiment was divided into four parts: a animals consumed ethanol in their home cage using the ethanol escalation model; b phase 1: following the establishment of baseline ethanol consumption using the DID method animals were divided into two groups with group A receiving GSK1521498 and group B receiving naltrexone as the test compound; c phase 2: following a 2-week wash-out period, DID was re-established and a cross-over design was employed such that group A received naltrexone and group B received GSK1521498 as the test compound; d compound specificity was tested using a 2 % sucrose DID protocol

Mentions: Following home cage ethanol consumption using the intermittent ethanol escalation model, and 1-week habituation to the shifted light/dark cycle (lights off at 11 am), the animals were trained to drink in the dark a 20 % ethanol solution from spring loaded sipper tubes over a 3-week period, using a 2-day intermittent DID procedure (Kamdar et al. 2007; see Fig. 1 for an overview of the DID protocol).Fig. 1


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)

Overview of the experimental protocol. The experiment was divided into four parts: a animals consumed ethanol in their home cage using the ethanol escalation model; b phase 1: following the establishment of baseline ethanol consumption using the DID method animals were divided into two groups with group A receiving GSK1521498 and group B receiving naltrexone as the test compound; c phase 2: following a 2-week wash-out period, DID was re-established and a cross-over design was employed such that group A received naltrexone and group B received GSK1521498 as the test compound; d compound specificity was tested using a 2 % sucrose DID protocol
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Overview of the experimental protocol. The experiment was divided into four parts: a animals consumed ethanol in their home cage using the ethanol escalation model; b phase 1: following the establishment of baseline ethanol consumption using the DID method animals were divided into two groups with group A receiving GSK1521498 and group B receiving naltrexone as the test compound; c phase 2: following a 2-week wash-out period, DID was re-established and a cross-over design was employed such that group A received naltrexone and group B received GSK1521498 as the test compound; d compound specificity was tested using a 2 % sucrose DID protocol
Mentions: Following home cage ethanol consumption using the intermittent ethanol escalation model, and 1-week habituation to the shifted light/dark cycle (lights off at 11 am), the animals were trained to drink in the dark a 20 % ethanol solution from spring loaded sipper tubes over a 3-week period, using a 2-day intermittent DID procedure (Kamdar et al. 2007; see Fig. 1 for an overview of the DID protocol).Fig. 1

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