Friday, May 16, 2025
5/16/2025
Influence of Orexin Antagonism on Motivation for Alcohol - 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.
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