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Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats
Open accessAbstract
Orexins are hypothalamic neuropeptides which bind to two G-protein-coupled receptors, orexin-1 (OX(1)R) and orexin-2 (OX(2)R) receptor. While a role for OX(1)R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX(2)R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX(2)R in ethanol-taking and ethanol-seeking behaviour. Indiana ethanol-preferring rats were trained to self-administer ethanol (10% w/v) or sucrose (0.7–1% w/v) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. The selective OX(2)R antagonist TCS-OX2-29 was administered i.c.v. to assess its effect on operant self-administration and cue-induced reinstatement following extinction. Following i.c.v. injection TCS-OX2-29 reduced self-administration of ethanol, but not sucrose. Despite reducing ethanol self-administration, TCS-OX2-29 had no impact on cue-induced reinstatement of ethanol seeking. To determine where in the brain OX(2)R were acting to modulate ethanol self-administration, TCS-OX2-29 was microinjected into either the shell or core of the nucleus accumbens (NAc). Intra-NAc core, but not shell, infusions of TCS-OX2-29 decreased responding for ethanol. Importantly, the doses of TCS-OX2-029 used were non-sedating. Collectively, these findings implicate OX(2)R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX(2)R had no impact on sucrose self-administration. Thus, OX(2)R in addition to OX(1)R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX(1)R, no impact of OX(2)R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX(2)R in ethanol self-administration compared to cue-conditioned ethanol-seeking.
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“Both Hcrt-1 and Hcrt-2 receptor blockade decreased alcohol self-administration in alcohol-preferring rats(Lawrence et al., 2006;Brown et al., 2013).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Brown et al., 2013
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Metadata
- Authors
- Brown, R. M., Khoo, S. Y.-S., & Lawrence, A. J.
- Affiliations
- Medical University of South Carolina (US)
- The University of Melbourne (AU)
- Corresponding author
- Lawrence, Andrew John
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-10-01
- Volume
- 16
- Issue
- 9
- Pages
- 2067-2079
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W1987854393
- Cited by
- 101
- References
- 75
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 6 · 2016: 12 · 2015: 10 · 2014: 10 · 2013: 1
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- State Government of Victoria
- Medical Research Council
- National Health and Medical Research Council (1021227)
- 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 receptor 2, TCS OX2 29, ethanol self-administration, ethanol seeking, cue-induced reinstatement, nucleus accumbens, nucleus accumbens shell, nucleus accumbens core, ethanol reinforcement, sucrose self-administration, alcoholism, G protein-coupled receptors
- MeSH terms
- Orexin Receptor Antagonists, Alcohol Drinking, Ethanol, Animals, Behavior, Animal, Brain, Conditioning, Psychological, Cues, Isoquinolines, Male, Motor Activity, Pyridines, Reward, Self Administration, Sucrose, Rats, Drug-Seeking Behavior, Orexin Receptors
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