Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats
Open accessAbstract
The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short- (1 h; ShA) or long- (12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.
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Hcrt-2 receptor mRNA levels increased in the CeA in long-access rats.
“Additionally, an increase in Hcrt-2 receptor mRNA levels in the CeA in longaccess rats was observed by quantitative polymerase chain reaction.”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Schmeichel et al., 2015
The Results section reports that Hcrtr2 mRNA increased in the amygdala of long-access rats, measured by qPCR. The Reverse Transcription and Quantitative PCR section says amygdala substructures were not assessed, so the paper does not establish an increase specifically in the CeA. Page numbers are unavailable in our copy. (LLM, conf=0.92)
Experimental — accuracy not yet measuredSystemic administration of an Hcrt-2 receptor antagonist dose-dependently decreased heroin self-administration in long-access but not short-access animals.
“The systemic administration of an Hcrt-2 receptor antagonist dose-dependently decreased heroin self-administration in long-access but not in shortaccess animals in an extended-access procedure(Schmeichel et al., 2015).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Schmeichel et al., 2015
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- Authors
- Schmeichel, B. E., Barbier, E., Misra, K. K., Contet, C., Schlosburg, J. E., Grigoriadis, D., Williams, J. P., Karlsson, C., Pitcairn, C., Heilig, M., Koob, G. F., & Vendruscolo, L. F.
- Affiliations
- Scripps Research Institute (US)
- National Institutes of Health (US)
- Neurocrine Biosciences (United States) (US)
- Corresponding author
- Schmeichel, Brooke E
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2014-11-04
- Volume
- 40
- Issue
- 5
- Pages
- 1123-1129
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4367454
- OpenAlex
- W2008263329
- Cited by
- 79
- References
- 39
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 13 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA007456, T32AA007456)
- National Institute on Drug Abuse (K99DA037344, DA004398, DA-004043, R01DA004398, R01DA004043)
- 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 › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- hypocretin receptor 2, heroin self-administration, extended access, compulsive drug seeking, opioid use disorder, central amygdala, drug reinforcement
- MeSH terms
- Orexin Receptor Antagonists, Animals, Heroin, Disease Models, Animal, Dose-Response Relationship, Drug, Drinking Behavior, Feeding Behavior, Heroin Dependence, Locomotion, Male, Narcotics, RNA, Messenger, Self Administration, Substance Withdrawal Syndrome, Time Factors, Rats, Wistar, Drug-Seeking Behavior, Orexin Receptors, Central Amygdaloid Nucleus
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