The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice
Open accessAbstract
The orexin/hypocretin (ORX) system plays a major role in motivation for natural and drug rewards. In particular, a number of studies have shown that ORX signaling through the orexin 1 receptor (OX1R) regulates alcohol seeking and consumption. Despite the association between ORX signaling and motivation for alcohol, no study to date has investigated what role the ORX system plays in alcohol dependence, an understanding of which would have significant clinical relevance. This study was designed to evaluate the effect of the highly selective OX1R antagonist GSK1059865 on voluntary ethanol intake in ethanol-dependent and control non-dependent mice. Mice were subjected to a protocol in which they were evaluated for baseline ethanol intake and then exposed to intermittent ethanol or air exposure in inhalation chambers. Each cycle of chronic intermittent ethanol (CIE), or air, exposure was followed by a test of ethanol intake. Once the expected effect of increased voluntary ethanol intake was obtained in ethanol dependent mice, mice were tested for the effect of GSK1059865 on ethanol and sucrose intake. Treatment with GSK1059865 significantly decreased ethanol drinking in a dose-dependent manner in CIE-exposed mice. In contrast GSK1059865 decreased drinking in air-exposed mice only at the highest dose used. There was no effect of GSK1059865 on sucrose intake. Thus, ORX signaling through the OX1R, using a highly-selective antagonist, has a profound influence on high levels of alcohol drinking induced in a dependence paradigm, but limited or no influence on moderate alcohol drinking or sucrose drinking. These results indicate that the ORX system may be an important target system for treating disorders of compulsive reward seeking such as alcoholism and other addictions in which motivation is strongly elevated.
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Hcrt-1 receptor antagonist dose-dependently decreased alcohol intake, particularly in alcohol-dependent mice.
“The Hcrt-1 receptor antagonist dosedependently decreased alcohol intake, particularly in alcohol-dependent mice(Lopez et al., 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Lopez et al., 2016
The Results report that GSK1059865 reduced ethanol intake at every tested dose in ethanol-dependent mice, but only at the highest dose in non-dependent controls. This supports the greater sensitivity of dependent mice; the Results do not establish that intake decreased progressively as dose increased. (LLM, conf=0.82)
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Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
Koob, G. F. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000083 · Cited by 337 · see citing works
- Authors
- Lopez, M. F., Moorman, D. E., Aston-Jones, G., & Becker, H. C.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Lopez, Marcelo F.
- Moorman, David E.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 1636
- Pages
- 74-80
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC4808605
- OpenAlex
- W2270610401
- Cited by
- 62
- References
- 61
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 11 · 2017: 4 · 2016: 6
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- PHS (P50-AA010761, U01-AA014095, U01-AA020929, R21-DA032005, R37/R01-DA006214, UL1-RR029882)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- orexin-1 receptor, alcoholism, ethanol consumption, chronic intermittent ethanol, alcohol seeking, reward motivation, sucrose intake, addiction treatment targets
- MeSH terms
- Orexin Receptor Antagonists, Alcohol Drinking, Ethanol, Aminopyridines, Analysis of Variance, Animals, Dose-Response Relationship, Drug, Drinking Behavior, Male, Mice, Inbred C57BL, Piperidines, Sucrose, Mice
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