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

Relapse to cocaine use after abstinence remains a significant challenge for treating cocaine use disorder. While the mechanisms of relapse are still under investigation, adaptations in mesolimbic dopamine systems may contribute to cocaine craving and propensity for relapse. Current pharmacological treatments targeting dopamine systems are often intolerable and may have abuse potential. Therefore, identifying novel pharmacological targets for cocaine use disorder is crucial. The hypocretin/orexin system has been shown to regulate cocaine-associated behavior and dopamine transmission. Our previous studies indicated that the hypocretin receptor 1 antagonist, RTIOX-276, reduced motivation for cocaine and attenuated dopamine responses to cocaine. Importantly, the effects of RTIOX-276 on dopamine transmission persisted for at least 24 hours, suggesting lasting effects of hypocretin receptor antagonism. Here, we hypothesized that a single RTIOX-276 treatment would reduce motivation for cocaine and normalize dopamine transmission after abstinence. Rats were pre-assessed for cocaine consumption and motivation using a within-session threshold schedule before intermittent access exposure to cocaine. Rats were subsequently 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 normalized 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.