Shaw, J. K. | bioRxiv Science

bioRxiv2024

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.

neuroscience↗

bioRxiv2022

Strawberry additive increases nicotine vapor sampling and systemic exposure but does not enhance Pavlovian-based nicotine reward in mice

Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, due to the availability of electronic nicotine devices (i.e., "vaping") and nicotine e-liquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine + strawberry additive vapor had higher plasma cotinine concentrations, which did not appear to reflect altered nicotine metabolism. Instead, by directly measuring vapor sampling through respiration monitoring, we uncovered an increase in the amount of sniffing toward strawberry-containing nicotine vapor compared to nicotine vapor alone. Together these data indicate that chemosensory-rich e-liquid additives may enhance the perceived sensory profile of nicotine vapors rather than the reward value per se, which leads to overall increased nicotine exposure. Significance StatementWith the rise in popularity of flavored e-cigarette products, many have considered the possibility that flavor volatiles will enhance nicotine reward; however, the possibility that flavor additives have chemosensory properties that can affect nicotine intake has been largely overlooked. Here, by delivering nicotine to adolescent mice as a vapor we were able to consider both possibilities. We found that mice had increased sniffing intensity and nicotine exposure when vapors contained a strawberry additive, despite the fact that the same additive was unable to enhance Pavlovian nicotine reward using a CPP paradigm. This research highlights the importance of considering the chemosensory properties of e-cigarette additives as a mechanism for their effect on nicotine use.

neuroscience↗