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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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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
The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases
Wang, C., Wang, Q., Ji, B., Pan, Y., Xu, C., Cheng, B., Bai, B., & Chen, J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00220 · Cited by 219
Orexin/hypocretin role in reward: implications for opioid and other addictions
Baimel, C., Bartlett, S. E., Chiou, L., Lawrence, A. J., Muschamp, J. W., Patkar, O. L., Tung, L.-W., & Borgland, S. L. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12639 · Cited by 183
Self-citationA Decade of Orexin/Hypocretin and Addiction: Where Are We Now?
James, M. H., Mahler, S. V., Moorman, D. E., & Aston‐Jones, G. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_57 · Cited by 175
Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder
Burnette, E. M., Nieto, S. J., Grodin, E. N., Meredith, L. R., Hurley, B., Miotto, K., Gillis, A. J., & Ray, L. A. (2022) · Drugs · doi:10.1007/s40265-021-01670-3 · Cited by 169
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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