Journal article
Hypocretin receptor 1 blockade early in abstinence reduces future demand for cocaine
Neuropharmacology, v 291, 110898
27 Feb 2026
PMID: 41765282
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Relapse to cocaine use after periods of abstinence remains a significant challenge for treating cocaine use disorder. While the neurobiological mechanisms underlying relapse are still under investigation, adaptations in mesolimbic dopamine systems may contribute to cocaine craving and propensity for relapse. Therefore, reversing or preventing these dopamine adaptations may reduce motivation for cocaine and decrease the likelihood of relapse. The hypocretin/orexin system has been shown repeatedly to regulate cocaine-associated behavior and dopamine transmission. For example, our previous studies indicated that the hypocretin receptor 1 antagonist-RTIOX-276-reduced behavioral and dopamine responses to cocaine. Importantly, the effects of RTIOX-276 on dopamine transmission persisted for at least 24 hr, suggesting lasting effects of hypocretin receptor antagonism. Here, we hypothesized that a single RTIOX-276 treatment early in abstinence would reduce motivation for cocaine and prevent alterations in dopamine transmission later in abstinence. Female and male rats were pre-assessed for cocaine consumption and motivation using a within-session threshold schedule before undergoing 7 days of intermittent access to cocaine. After intermittent access self-administration, rats were treated with RTIOX-276 on the first day of a 7-day abstinence period, after which they were reassessed for cocaine consumption and motivation or examined for dopamine transmission using fast-scan cyclic voltammetry in nucleus accumbens core slices. We found that a single treatment with RTIOX-276 on the first day of abstinence reduced motivation for cocaine and prevented aberrant dopamine uptake observed following intermittent access to cocaine. These findings suggest that hypocretin receptor 1 may be a viable target for reducing motivation for cocaine through alterations in dopamine transmission in the nucleus accumbens.
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Details
- Title
- Hypocretin receptor 1 blockade early in abstinence reduces future demand for cocaine
- Creators
- Shanna B Samels - Drexel UniversityJessica K Shaw - Drexel UniversityI Pamela Alonso - Drexel UniversityEmily M Black - Haverford CollegeYanan Zhang - RTI InternationalRodrigo A España - Drexel University
- Publication Details
- Neuropharmacology, v 291, 110898
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Number of pages
- 9
- Grant note
- National Institute on Drug Abuse: R01DA039100 National Institute on Alcohol Abuse and Alcoholism: R01AA030509 National Science Foundation Graduate Research Fellowship Program: 2041772
We thank the National Institute on Drug Abuse drug supply program for donating the cocaine hydrochloride. This work was supported by the National Institute on Drug Abuse grants R01DA039100 (RAE) and the National Institute on Alcohol Abuse and Alcoholism grants R01AA030509 (YZ). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 2041772. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:001712545300001
- Scopus ID
- 2-s2.0-105031854305
- Other Identifier
- 991022166401304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy