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The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.
Psychopharmacology (Berl). 2015 Sep; 232(18):3431-41.P

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.

Authors+Show Affiliations

School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26141191

Citation

Ripley, Tamzin L., et al. "The Novel Mu-opioid Antagonist, GSK1521498, Reduces Ethanol Consumption in C57BL/6J Mice." Psychopharmacology, vol. 232, no. 18, 2015, pp. 3431-41.
Ripley TL, Sanchez-Roige S, Bullmore ET, et al. The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice. Psychopharmacology (Berl). 2015;232(18):3431-41.
Ripley, T. L., Sanchez-Roige, S., Bullmore, E. T., Mugnaini, M., Maltby, K., Miller, S. R., Wille, D. R., Nathan, P., & Stephens, D. N. (2015). The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice. Psychopharmacology, 232(18), 3431-41. https://doi.org/10.1007/s00213-015-3995-x
Ripley TL, et al. The Novel Mu-opioid Antagonist, GSK1521498, Reduces Ethanol Consumption in C57BL/6J Mice. Psychopharmacology (Berl). 2015;232(18):3431-41. PubMed PMID: 26141191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice. AU - Ripley,Tamzin L, AU - Sanchez-Roige,Sandra, AU - Bullmore,Edward T, AU - Mugnaini,Manolo, AU - Maltby,Kay, AU - Miller,Sam R, AU - Wille,David R, AU - Nathan,Pradeep, AU - Stephens,David N, Y1 - 2015/07/05/ PY - 2015/04/01/received PY - 2015/06/12/accepted PY - 2015/7/5/entrez PY - 2015/7/5/pubmed PY - 2016/3/18/medline SP - 3431 EP - 41 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 232 IS - 18 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/26141191/The_novel_mu_opioid_antagonist_GSK1521498_reduces_ethanol_consumption_in_C57BL/6J_mice_ L2 - https://dx.doi.org/10.1007/s00213-015-3995-x DB - PRIME DP - Unbound Medicine ER -