Abstract
The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.
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Acknowledgements
The authors would like to thank Rui Morimoto, Katy Lunny, Kyle Bullock, Michael Mirbaba, Lyric Tully, Kavya Mudiam, Tsu Xuan Wu, Xuan-Thanh Nguyen, Jessica Jenkins, and Taylor Rohrbaugh, for their contribution to the data collection for this project. Thank you to the UCLA Clinical and Translational Research Center nursing staff who were instrumental in all alcohol administration sessions. Thank you to Emily Hartwell, Aaron Lim, ReJoyce Green, and Jonathan Westman for their input on manuscript preparation. Support for the development of the Computer-Assisted Infusion System was provided by Sean O’Connor, Martin Plawecki, and Victor Vitvitskiy, Indiana Alcohol Research Center (P60 AA007611), Indiana University School of Medicine. The authors would also like to thank Bethany Stangl for her help in setting up the CAIS system. The authors would like to thank Jennifer Krull for her assistance in conceptualizing and implementing the statistical modeling and power analysis employed in this manuscript. Lastly the authors would like to thank Christopher Evans for his assistance in study conceptualization focusing on the translation of preclinical models to human research. Funding & Disclosures: This work was supported by the NIAAA (R21 - AA022752 to LAR). SB was supported as a pre-doctoral trainee and is receiving postdoctoral funding from the NIAAA (F31 - AA022569 to SB & R01 - DA041226 to LAR). LAR has received study medication from Pfizer and Medicinova and consulted for GSK. While there was no formal pre-registration of the study analyses (e.g., in the Open Science Framework), this study was proposed and served as the dissertation for the lead author (SB), and as such the full analytic plan, including the analyses that are presented in the final manuscript were discussed and decided a priori with a team of experts including a quantitative psychologist specializing in multilevel modeling (Jennifer Krull).
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Bujarski, S., Jentsch, J.D., Roche, D.J.O. et al. Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm. Neuropsychopharmacol 43, 1891–1899 (2018). https://doi.org/10.1038/s41386-018-0086-9
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DOI: https://doi.org/10.1038/s41386-018-0086-9
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