Human Alcohol Seeking Despite Aversion

Prolonged alcohol use results in drinking despite resultant problems and adverse consequences. The investigators propose to test a laboratory model of human seeking despite aversion to use as an early marker of disease onset, and as a tool for study of its neural functional substrates, and identification of effective treatments.

The long-term goal for this project is to establish a model of alcohol seeking despite aversion (SDA) as a platform for the laboratory testing of novel pharmacologic and behavioral interventions that can be used among those with the highest risk, but who have yet to progress to treatment-resistant drinking. The objective of this application is to test SDA across multiple levels of analysis. The investigators consider SDA as an early marker of alcohol use disorder progression that is related to lifetime drinking history, alcohol use disorder risks, and brain physiology. The investigators have completed a pilot study demonstrating that SDA can be objectively quantified via an intravenous alcohol self-administration task, in which operant work for identical incremental alcohol rewards is paired with aversive stimuli. This preliminary data supports the central hypotheses that behavior in the SDA model is attributable to lifetime alcohol exposure, is related to alcohol use disorder risk factors and phenotypes, and reflects alterations in neural system function. In this project, SDA will be measured along with recent drinking history, negative affect-based rash action (i.e. negative urgency, including action with respect to alcohol use), and self-rating of the effects of alcohol. The rationale for this work is that it would lead to the first objective, well-validated measure of SDA in humans.

Half of the participants will have a history of higher lifetime alcohol consumption; all will participate in both interventions (Aversive cue, Neutral cue).

Half of the participants will have a history of lower lifetime alcohol consumption; all will participate in both interventions (Aversive cue, Neutral cue).

Some participants will also complete a functional magnetic resonance imaging (fMRI) session to determine resting state connectivity. All participants in this Arm will have completed both of the iv alcohol self-administration sessions (Aversive cue, Neutral cue).

Participants will be exposed to unpleasant pictures and tones during performance of a task to earn alcohol

Participants will be exposed to neutral pictures and tones during performance of a task to earn alcohol

Between session differences in self-administration will be evaluated using progressive work breakpoint

Inclusion Criteria: Higher or lower lifetime alcohol drinking history Able to understand and complete questionnaires and procedures in English BMI between 18.5 and 32 Willing and able to tolerate iv placement Right-handed (for fMRI Arm only) Exclusion Criteria: Pregnant or breast-feeding Seeking or in treatment for substance use disorder or under court ordered abstinence Medications, medical disorders or conditions that could affect study outcome or subject safety Positive urine drug screen for amphetamines/methamphetamines, barbiturates, benzodiazepines, cocaine, opiates, or phencyclidine Positive breath alcohol (BrAC) reading on arrival at any study visit Actively suicidal (within previous year) Left-handed or ambidextrous (for fMRI Arm only)

After publication of the main findings, a de-identified dataset will be made available through direct requests as described above; a statement to this effect will be included in all published manuscripts. The current proposal utilizes the Seeking Despite Aversion Task, a newly developed Computer-Assisted Infusion System (CAIS) protocol that integrates delivery of visual stimuli into the Constant Attention Task and optical markers for evoked response potential generation. This task, like other CAIS protocols, will become part of the portfolio of CAIS programs that our lab makes available to other scientists once our specific funded use of this protocol is completed. Modified versions of this protocol could be provided to other investigators prior to completion of this project as long as these projects do not directly compete.

Data will become available following final publication of all manuscripts by the component investigators. Earliest date is estimated to be January, 2025.

Data and Resource Sharing Plan - Indiana Alcohol Research Center (IARC) Consistent with its past history, the IARC continues to make available its data and resources to investigators engaged in alcoholism research outside of Indiana University. Detailed procedures are available on request. In brief, investigators must submit a written request specifying in adequate detail the specific resource(s) required and a study protocol indicating the specific aims, scientific rationale, methods and procedure, and analysis of results; a signed IARC Resource Utilization Agreement Form; and for studies involving human subjects, Institutional Review Board (IRB) approval if needed for the proposed study. The request will be reviewed by the IARC Steering Committee. Investigators must agree to acknowledge the Indiana Alcohol Research Center (P60 AA007611) as the source of the resource in all resulting publications.