ABSTRACT
Alcohol use disorder (AUD) is an unrelenting public health concern. Despite great strides in understanding the
neurobiological underpinnings of problem alcohol use 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 AUD and to guide treatment based on those clinical neuroscience
findings. One area of intense interest in preclinical research is the role of the orexin system in addiction.
Through extrahypothalamic transmission, the orexin system plays a key part in motivation for maladaptive
rewards like drugs of abuse. In preclinical studies, exogenous administration of orexin peptides increases
alcohol self-administration. Conversely, pharmacological antagonism of the orexin system reduces effortful
responding maintained by alcohol (e.g., on a progressive-ratio schedule) and alcohol-seeking behavior, relative
to vehicle. Pharmacological antagonism of orexin receptors also ameliorates sleep disruptions caused by
chronic alcohol exposure. Preclinical findings further indicate administration of orexin antagonists generally
does not affect responding for non-alcohol rewards. Taken together, these preclinical findings suggest orexin
system antagonism selectively reduces motivation for alcohol, as well as other maladaptive alcohol-associated
behaviors. Although a robust preclinical literature indicates a key role of the orexin system in motivation for
alcohol, along with alcohol’s other pharmacodynamic effects, this area remains essentially unstudied in
humans, except for some observational studies showing altered peripheral orexin levels during alcohol
withdrawal. The overarching goal of this project is thus to translate promising preclinical findings into clinical
populations, thereby demonstrating the orexin system plays a key role in motivation for alcohol in humans. This
project will also determine the influence of orexin antagonism on other pharmacodynamic effects of alcohol,
including subjective response, performance, physiological response and sleep. The research proposed here
will directly translate findings from preclinical research and provide the initial clinical evidence that orexin
antagonism reduces motivation for alcohol and other alcohol-associated maladaptive behaviors in individuals
with AUD. This study will also provide basic science information about the orexinergic mechanisms underlying
the pharmacodynamic effects of alcohol in humans. As such, the outcomes will contribute to our understanding
of the clinical neurobiology of AUD. Overall, the proposed work seeks to expand the scope of current clinical
neuroscience research on AUD by focusing on orexin, which has strong preclinical evidence supporting its
critical role in addiction but remains largely unstudied in humans.