Grants and Contracts Details
Description
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 cocaineassociated
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.
Status | Finished |
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Effective start/end date | 5/1/19 → 4/30/23 |
Funding
- National Institute on Drug Abuse: $1,106,795.00
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