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Item Binge and High-Intensity Drinking – Associations with Intravenous Alcohol Self-Administration and Underlying Risk Factors(Wiley, 2022) Plawecki, Martin H.; Boes, Julian; Wetherill, Leah; Kosobud, Ann E.K.; Stangl, Bethany L.; Ramchandani, Vijay A.; Zimmermann, Ulrich S.; Nurnberger, John I., Jr.; Schuckit, Marc; Edenberg, Howard J.; Pandey, Gayathri; Kamarajan, Chella; Porjesz, Bernice; Foroud, Tatiana; O’Connor, Sean; Psychiatry, School of MedicineSome styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.Item Development and pilot validation of Computer-Assisted Self- Selfinfusion of Ethanol (CASE): a new method to study alcohol self- selfadministration in humans(Wiley, 2008-07) Zimmermann, Ulrich S.; Mick, Inge; Vitvitskiy, Victor; Plawecki, Martin H.; Mann, Karl F.; O’Connor, Sean; Psychiatry, School of MedicineBackground: Human alcohol self-administration studies employing oral intake are subject to high variability of the resulting blood alcohol concentrations because of idiosyncrasies of gastrointestinal absorption kinetics among subjects. We sought to improve the subjects' opportunity to control their brain alcohol exposure by computer-assisted i.v. self-administration. Methods: Instead of drinking, subjects could request increments of their arterial blood alcohol concentration (aBAC) of precisely 7.5 mg% at any time they wanted by pressing a button, provided their aBAC would not exceed 100 mg%. The latency between pushing the button and reaching the new aBAC peak was preset to be 2.5 minutes on the first day and was randomly changed to 1.5 or 3.5 minutes on days 2 and 3 in a crossover design. The necessary rate and amount of alcohol infusion was calculated by the software about once every second. Nine healthy social drinkers (4 females/5 males; mean age 25.0 +/- 4.0 year) participated in 3 sessions each. Outcome measures were mean and maximum observed aBAC, and the number of alcohol requests. Results: Maximum aBAC was 76.5 +/- 26.3 mg% on average over all experiments. When grouping days 2 and 3 according to latency (1.5 vs. 3.5 minutes), maximum aBAC and the number of requests in the session were significantly higher with the faster rise and all 3 outcome measures were significantly correlated between days. No such correlations were found between the first and either of the following days. Conclusions: These data suggest that CASE is practical and safe, and results in considerable alcohol exposure that can be manipulated with parameters chosen for the incremental exposure. Following 1 practice day, test-retest stability was good, suggesting a potential for use in scientific studies.Item Offspring of parents with an alcohol use disorder prefer higher levels of brain alcohol exposure in laboratory experiments involving computer-assisted self-infusion of ethanol (CASE)(SpringerLink, 2009-03) Zimmermann, Ulrich S.; Mick, Inge; Laucht, Manfred; Vitvitskiy, Victor; Plawecki, Martin H.; Mann, Karl F.; O’Connor, Sean; Psychiatry, School of MedicineRationale: Acute alcohol effects may differ in social drinkers with a positive family history of alcohol use disorders (FHP) compared to FH negative (FHN) controls. Objectives: To investigate whether FHP subjects prefer higher levels of brain alcohol exposure than do FHN controls. Materials and methods: Twenty-two young healthy nondependent social drinkers participated in two identical sessions of computer-assisted self-infusion of ethanol (CASE); the first for practicing the procedures, the second to test hypotheses. All 12 FHP (four women) and ten FHN (three women) participants received a priming exposure, increasing arterial blood alcohol concentration (aBAC) to 30 mg% at 10 min and decreasing it to 15 mg% at 25 min. A 2-h self-administration period followed, during which only the subjects could increase their aBAC by pressing a button connected to a computer controlling the infusion pump. Infusion rate profiles were calculated instantaneously to increase aBAC by precisely 7.5 mg% within 2.5 min after each button press, followed by a steady descent. Subjects were instructed to produce the same alcohol effects as they would do at a weekend party. Results: The mean and maximum aBAC during the self-administration period and the number of alcohol requests (NOAR) were significantly higher in the FHP vs. FHN participants. Conclusions: This is the first laboratory experiment demonstrating higher alcohol self-administration in FHP compared to FHN subjects. A practice session increases the sensitivity of CASE experiments for detection of subtle differences in human alcohol self-administration.Item Striatal activity correlates with stimulant-like effects of alcohol in healthy volunteers(Springer Nature, 2018-08-01) Weafer, Jessica; Ross, Thomas J.; O’Connor, Sean; Stein, Elliot A.; de Wit, Harriet; Childs, Emma; Psychiatry, School of MedicineArticle Published: 01 August 2018 Striatal activity correlates with stimulant-like effects of alcohol in healthy volunteers Jessica Weafer, Thomas J. Ross, Sean O’Connor, Elliot A. Stein, Harriet de Wit & Emma Childs Neuropsychopharmacology volume 43, pages2532–2538(2018)Cite this article 366 Accesses 4 Citations 1 Altmetric Metricsdetails Abstract Individuals who experience greater stimulation and less sedation from alcohol are at increased risk for alcohol-related problems. However, little is known regarding the neurobiological mechanisms underlying subjective response to alcohol. The current study examined the degree to which alcohol-induced brain activation correlates with ratings of stimulation and sedation, using a within-subjects, double-blind, placebo-controlled design. Participants (N = 34 healthy adults with no history of alcohol use disorder) completed three sessions: a calibration session to determine the duration of infusion needed to bring the breath alcohol to 80 mg/dl for each subject, and two counterbalanced fMRI sessions with placebo and alcohol administration. During the fMRI sessions, participants underwent 50 min scans, which included a 10 min baseline period, the IV infusion period needed to bring breath alcohol concentration (BrAC) to a peak 80 mg/dl (on the alcohol session), followed by a post-peak decline period. Participants rated their subjective stimulation and sedation at regular intervals throughout the scan. A priori VOI analyses showed that the time course of stimulation correlated with BOLD signal in the striatum. The time course of sedation did not correlate with BOLD signal in any VOIs. There were no correlations in primary visual cortex, which served as a control. These findings are the first to show that alcohol effects in the striatum are linked to the positive, stimulant-like effects of the drug and advance our understanding of the neurobiological mechanisms underlying individual differences in subjective responses to alcohol, and more broadly, risk for alcohol use disorders.Item Transportation Active Safety Institute(Office of the Vice Chancellor for Research, 2010-04-09) Ainslie, Paul; Chen, Yaobin; Justiss, Michael; Koskie, Sarah; O’Connor, SeanSince its founding in February 2006, the mission of the Transportation Active Safety Institute (TASI) has been to advance the use of active safety systems to reduce vehicle crashes and save lives. TASI was one of 10 centers awarded IUPUI Signature Center funding in January, 2008. With core faculty drawn from ten departments representing eight schools, the Transportation Active Safety Institute (TASI) is a university-wide interdisciplinary center for advanced automotive-safety research and development on the IUPUI campus. Partnership with industry, government, and non-profit agencies ensures that university research activities complement existing technologies and address existing and future needs. TASI aims to provide a neutral forum for pre-competitive discussion and development of standards and test methodologies for establishing objective benefits of active-safety systems. TASI has established a driving simulator laboratory for research into driver behavior and for testing active-safety system performance. The state-of-the-art DriveSafety DS-600c Driving Simulator is providing a flexible and realistic driving environment for industry, government, and internally sponsored research. This reconfigurable platform allows TASI to test various sensors and driver interfaces, in order to determine effective and convenient solutions to challenges in enhancing safety. TASI held its third workshop, the International Workshop on Research in Active Safety Technology, August 10-11, 2009, in Indianapolis and is currently planning an international workshop on human factors for August 2010. TASI has established an active dialog with other vehicle safety centers around the world through our Global Academic Network for Active Safety.Item Transportation Active Safety Institute(Office of the Vice Chancellor for Research, 2011-04-08) Chen, Yaobin; Justiss, Michael; Koskie, Sarah; O’Connor, SeanSince its founding in February 2006, the mission of the Transportation Active Safety Institute (TASI) has been to advance the use of active safety systems to reduce vehicle crashes and save lives. TASI was one of 10 centers awarded IUPUI Signature Center funding (second round) in January, 2008. With core faculty drawn from ten departments representing eight schools at IUPUI, IUB and PUWL, the Transportation Active Safety Institute (TASI) is an interdisciplinary center for advanced transportation safety research and development on the IUPUI campus. Partnership with industry, government, and non-profit agencies ensures that university research activities complement existing technologies and address existing and future needs. TASI aims to provide a neutral forum for pre-competitive discussion and development of standards and test methodologies for establishing objective benefits of active-safety systems. TASI has established a driving simulator laboratory for research into driver behavior and for testing active safety system performance. The state-of-the-art DriveSafety DS-600c Driving Simulator is providing a flexible and realistic driving environment for industry, government, and internally sponsored research. This reconfigurable platform allows TASI to test various sensors and driver interfaces, in order to determine effective and convenient solutions to challenges in enhancing safety. Faculty members, research staff and graduate students have been working on several funded research projects such as human factors for semi-autonomous driving systems, intelligent human vehicle interfaces, real vehicle testing for crash-imminent braking system (autonomous braking system), distracted and impaired driving assessment, teen and older driver safety research, dealing with uncertainty in autonomous braking system, etc. TASI has also established an active dialog with other vehicle safety centers around the world through our “Global Academic Network for Active Safety.” Currently, global academic partners include Center for Automotive Research at the Ohio State University, National Advanced Driving Simulator at University of Iowa, University of Wisconsin, Tsinghua University in China, and Chalmers University of Technology in Sweden.Item Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial(Springer Nature, 2023-04-05) Spreer, Maik; Grählert, Xina; Klut, Ina-Maria; Al Hamdan, Feras; Sommer, Wolfgang H.; Plawecki, Martin H.; O’Connor, Sean; Böttcher, Michael; Sauer, Cathrin; Smolka, Michael N.; Zimmermann, Ulrich S.; Psychiatry, School of MedicineThis registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen's d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = -0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen's d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone's effect might depend on reward contingency.