Insular hypocretin transmission regulates nicotine reward
Open accessAbstract
Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.
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Blockade of hypocretin-1 receptors in the pGIC attenuates nicotine, but not food, taking.
“Similar attenuation of nicotine, but not food, taking has been demonstrated by blockade of hypocretin-1 receptors in the pGIC”
From The Insula: A Brain Stimulation Target for the Treatment of Addiction (2019) · cites this paper as Hollander et al., 2008
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- Authors
- Hollander, J. A., Lu, Q., Cameron, M. D., Kamenecka, T. M., & Kenny, P. J.
- Affiliations
- Scripps Research Institute (US)
- Molecular Therapeutics and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-09
- Volume
- 105
- Issue
- 49
- Pages
- 19480-19485
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2614786
- OpenAlex
- W1967108382
- Cited by
- 296
- References
- 34
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 9 · 2020: 30 · 2019: 11 · 2018: 18 · 2017: 12 · 2016: 15 · 2015: 20 · 2014: 18 · 2013: 25 · 2012: 29
- FWCI
- 10.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA030929, DA020686, R01DA020686, DA023915, R01DA023915, F32DA024932, DA024932, R37DA020686)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- orexin, insula, nicotine reward, nicotine self-administration, tobacco dependence, drug reinforcement, intracranial self-stimulation
- MeSH terms
- Orexins, Animals, Benzoxazoles, Cerebral Cortex, Male, Motivation, Naphthyridines, Synaptic Transmission, Neuropeptides, Nicotine, Reward, Self Administration, Smoking, Tobacco Use Disorder, Urea, Rats, Wistar, Receptors, Neuropeptide, Nicotinic Agonists, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Rats, Orexin Receptors
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