Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm

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.

Fig. 1

Subject Flow diagram and recruitment overview

Fig. 2

Individual BrAC curves computed via the Computerized Alcohol Infusion System (CAIS). CAIS implements a physiologically based pharmacokinetic model to estimate BrAC pseudo-continuously (30-s intervals) based on the infusion time course and participants sex, age, height, weight, and real-time breathalyzer readings. The alcohol administration paradigm consisted of two components. The alcohol challenge to target BrACs = 20, 40, and 60 mg%, lasted on an average of 70.66 (SD = 5.20) min, and the self-administration paradigm lasted an average of 100.42 (SD = 5.10) min. Participants completed SR measures at each challenge time point

Fig. 3

Magnitude of subjective responses to alcohol over the Challenge. Each graph represents the expected value of the subjective response variable estimated from a multilevel model including the predictors of alcohol use severity, BrAC time point, and their interaction. a The Stimulation outcome was a combined outcome including the measures, BAES Stimulation, POMS Vigor, and POMS Positive Mood. b The Sedation outcome was combined from the BAES Sedation and SHAS scales. c Negative Affect combined POMS Tension and Negative Mood. d Alcohol craving was measured using the AUQ. The selected alcohol use Severity factor scores correspond to the mean values for participants who had no current AUD diagnosis (−1.26), mild AUD (−0.05), moderate AUD (1.57), and severe AUD (4.14) according to DSM-5

Fig. 4

Alcohol use severity was found to predict greater BrAC curves over the course of the alcohol self-administration. BrAC levels were estimated by the CAIS software in 30-s intervals; however, for analyses, these estimated BrAC values were averaged over 10 min bins. The displayed lines represent the predicted values according to the final multilevel including a quartic time trend, alcohol use severity factor score, and the interaction between alcohol use severity and linear through cubic time terms. The selected alcohol use severity factor scores represent the mean scores for each DSM-5 AUD severity classifications (none = −1.26, mild = −0.05, moderate = 1.57, and severe = 4.14)

Fig. 5

Final model with craving level and alcohol use severity predicting BrAC self-administration curves. Craving level significantly predicted BrAC curve parameters. After accounting for alcohol craving level, alcohol use severity no longer predicted self-administration curves. The selected alcohol use severity factor scores represent the mean scores for each DSM-5 AUD severity classifications (none = −1.26, mild = −0.05, moderate = 1.57, and severe = 4.14)