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Hypocretin receptor 1 blockade early in abstinence reduces future demand for cocaine
Journal article   Peer reviewed

Hypocretin receptor 1 blockade early in abstinence reduces future demand for cocaine

Shanna B Samels, Jessica K Shaw, I Pamela Alonso, Emily M Black, Yanan Zhang and Rodrigo A España
Neuropharmacology, v 291, 110898
27 Feb 2026
DOI: https://doi.org/10.1016/j.neuropharm.2026.110898
PMID: 41765282

Abstract

FSCV Motivation Dopamine transporter Hypocretin Orexin Dopamine Cocaine
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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