Influence of Orexin Antagonism on Motivation for Cocaine

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ABSTRACT Cocaine use disorder continues to be a significant public health concern. Despite great strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings into clinical populations. Such translation is crucial to identify neurobiological circuits that contribute to the problems posed by cocaine use disorder and guide treatment based on those clinical neuroscience findings. One area of intense interest in preclinical research is the role of the orexin (also known as hypocretin) system in addiction. Through extrahypothalamic transmission, the orexin system plays a key part in motivation for maladaptive rewards like drugs of abuse. Antagonism of the orexin system attenuates motivation for cocaine, escalation of cocaine intake and reinstatement of cocaine seeking behavior. The first and only clinically available orexin antagonist, suvorexant (Belsomra®), attenuates motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding in non-human animals. Orexin antagonism generally does not alter adaptive behaviors like food or water intake, nor does it change cocaine-induced locomotion. Taken together, these preclinical findings suggest that orexin system antagonism selectively reduces motivation for cocaine, as well as other maladaptive cocaine-associated behaviors. Although a robust preclinical literature supports the premise that orexin antagonism attenuates motivation for cocaine, along with cocaine’s other abuse-related effects, this area remains unstudied in humans. The overarching goal of this project is to translate promising preclinical findings into clinical populations, thereby demonstrating that the orexin system plays a key role in motivation for cocaine in humans. To this end, non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine in experimental sessions following maintenance on a range of oral suvorexant doses. A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. After sampling a cocaine dose, subjects will make choices between that dose and an alternative reinforcer on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the relative influence of orexin antagonism on motivation to obtain these two types of reinforcers. A battery of subjective drug-effect measures and cognitive tasks will also be completed to evaluate how orexin antagonism influences other cocaine- associated outcomes in humans. This research will translate findings from preclinical research and provide the initial evidence that orexin antagonism reduces motivation for cocaine, as well as other cocaine-associated maladaptive behaviors in active cocaine users. The proposed work seeks to expand the scope of current clinical neuroscience research on cocaine addiction by focusing on orexin.