A multi-reward framework to improve translation in alcohol use disorder.

BACKGROUND AND OBJECTIVES: Alcohol use disorder (AUD) is a major contributor to global disease burden and a leading cause of preventable death, yet available treatments remain only modestly effective. Although rodent models are widely used to study alcohol-related behaviors and guide pharmacotherapy development, many compounds with strong preclinical efficacy fail clinically. Here, we propose a reward-component framework that separates ethanol intake into four distinct reward components: pre-oral reward, oral reward, post-oral peripheral reward, and post-oral central drug reward. We use this framework to examine whether cross-species differences in the reward components sustaining ethanol intake contribute to translational failure.

METHODS: We synthesized behavioral, pharmacological, and neurobiological evidence concerning the contribution of these four reward components to ethanol intake in rodents and humans with AUD, and compared findings across species.

RESULTS: The reward component primarily sustaining high ethanol intake in rodents remains largely unclear, with mixed contributions from oral and post-oral rewards. In contrast, AUD in humans is predominantly sustained by the post-oral central drug reward component, creating a cross-species misalignment in what rewards ethanol intake. Since pharmacotherapies differentially act across multiple components, this cross-species misalignment in reward components involved in ethanol intake between rodents and humans may explain previous translational failures in AUD pharmacotherapy development.

CONCLUSIONS: By offering a deeper understanding of past translational failures, this framework provides a basis for developing more valid and predictive preclinical models. Notably, identifying more effective pharmacological interventions will require improved alignment of the reward components controlling ethanol intake in animals and humans with AUD.