Browsing by Author "O’Connor, Sean J."

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    Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking
    (Wiley Blackwell (Blackwell Publishing), 2015-07) Kosobud, Ann E. K.; Wetherill, Leah; Plawecki, Martin H.; Kareken, David A.; Liang, Tiebing; Nurnberger, John L.; Windisch, Kyle; Xuei, Xiaoling; Edenberg, Howard J.; Foroud, Tatiana M.; O’Connor, Sean J.; Department of Psychiatry, IU School of Medicine
    BACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.
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    Correction: High-intensity sweet taste as a predictor of subjective alcohol responses to the ascending limb of an intravenous alcohol prime: an fMRI study
    (Springer Nature, 2024) Alessi, Jonathan; Dzemidzic, Mario; Benson, Katherine; Chittum, George; Kosobud, Ann; Harezlak, Jaroslaw; Plawecki, Martin H.; O’Connor, Sean J.; Kareken, David A.; Neurology, School of Medicine
    Correction to: Neuropsychopharmacology 10.1038/s41386-023-01684-3, published online 07 August 2023 The publication date for reference 21 was corrected from 2016 to 1977. The correct reference should read “Radloff LS. The CES-D Scale. Appl Psychol Meas. 1977;1:385–401”. The original article has been corrected.
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    Effects of acute alcohol exposure and chronic alcohol use on neurite orientation dispersion and density imaging (NODDI) parameters
    (Springer, 2023) Yoder, Karmen K.; Chumin, Evgeny J.; Mustafi, Sourajit M.; Kolleck, Kelly A.; Halcomb, Meredith E.; Hile, Karen L.; Plawecki, Martin H.; O’Connor, Sean J.; Dzemidzic, Mario; Wu, Yu‑Chien; Radiology and Imaging Sciences, School of Medicine
    Rationale: Little is known about how acute and chronic alcohol exposure may alter the in vivo membrane properties of neurons. Objectives: We employed neurite orientation dispersion and density imaging (NODDI) to examine acute and chronic effects of alcohol exposure on neurite density. Methods: Twenty-one healthy social drinkers (CON) and thirteen nontreatment-seeking individuals with alcohol use disorder (AUD) underwent a baseline multi-shell diffusion magnetic resonance imaging (dMRI) scan. A subset (10 CON, 5 AUD) received dMRI during intravenous infusions of saline and alcohol during dMRI. NODDI parametric images included orientation dispersion (OD), isotropic volume fraction (ISOVF), and corrected intracellular volume fraction (cICVF). Diffusion tensor imaging metrics of fractional anisotropy and mean, axial, and radial diffusivity (FA, MD, AD, RD) were also computed. Average parameter values were extracted from white matter (WM) tracts defined by the Johns Hopkins University atlas. Results: There were group differences in FA, RD, MD, OD, and cICVF, primarily in the corpus callosum. Both saline and alcohol had effects on AD and cICVF in WM tracts proximal to the striatum, cingulate, and thalamus. This is the first work to indicate that acute fluid infusions may alter WM properties, which are conventionally believed to be insensitive to acute pharmacological challenges. It also suggests that the NODDI approach may be sensitive to transient changes in WM. The next steps should include determining if the effect on neurite density differs with solute or osmolality, or both, and translational studies to assess how alcohol and osmolality affect the efficiency of neurotransmission.
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    Family history of alcoholism interacts with alcohol to affect brain regions involved in behavioral inhibition
    (Springer, 2013) Kareken, David A.; Dzemidzic, Mario; Wetherill, Leah; Eiler, William, II; Oberlin, Brandon G.; Harezlak, Jaroslaw; Wang, Yang; O’Connor, Sean J.; Neurology, School of Medicine
    Rationale: Impulsive behavior is associated with both alcohol use disorders and a family history of alcoholism (FHA). One operational definition of impulsive behavior is the stop-signal task (SST) which measures the time needed to stop a ballistic hand movement. Objective: Employ functional magnetic resonance imaging (fMRI) to study right frontal responses to stop signals in heavy drinking subjects with and without FHA, and as a function of alcohol exposure. Methods: Twenty-two family history-positive (FHP; age = 22.7 years, SD = 1.9) and 18 family history-negative (FHN; age = 23.7, SD = 1.8) subjects performed the SST in fMRI in two randomized visits: once during intravenous infusion of alcohol, clamped at a steady-state breath alcohol (BrAC) concentration of 60 mg/dL, and once during infusion of placebo saline. An independent reference group (n = 13, age = 23.7, SD = 1.8) was used to identify a priori right prefrontal regions activated by successful inhibition (Inh) trials, relative to "Go" trials that carried no need for inhibition [Inh > Go]. Results: FHA interacted with alcohol exposure in right prefrontal cortex, where alcohol reduced [Inh > Go] activation in FHN subjects but not in FHP subjects. Within this right frontal cortical region, stop-signal reaction time also correlated negatively with [Inh > Go] activation, suggesting that the [Inh > Go] activity was related to inhibitory behavior. Conclusions: The results are consistent with the low level of response theory (Schuckit, J Stud Alcohol 55:149-158, 1980; Quinn and Fromme, Alcohol Clin Exp Res 35:1759-1770, 2011), with FHP being less sensitive to alcohol's effects.
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    High-intensity sweet taste as a predictor of subjective alcohol responses to the ascending limb of an intravenous alcohol prime: an fMRI study
    (Springer Nature, 2024) Alessi, Jonathan; Dzemidzic, Mario; Benson, Katherine; Chittum, George; Kosobud, Ann; Harezlak, Jaroslaw; Plawecki, Martin H.; O’Connor, Sean J.; Kareken, David A.; Neurology, School of Medicine
    High-intensity sweet-liking has been linked to alcohol use disorder (AUD) risk. However, the neural underpinning of this association is poorly understood. To find a biomarker predictive of AUD, 140 participants (social and heavy drinkers, ages 21-26) underwent functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task and stimulation with high (SucroseHigh)- and low-concentration sucrose, as well as viscosity-matched water. On another day after imaging, and just before free-access intravenous alcohol self-administration, participants experienced a 30 mg% alcohol prime (10 min ascent) using the Computerized Alcohol Infusion System. Principal component analysis (PCA) of subjective responses (SR) to the prime's ascending limb generated enjoyable (SRenjoy) and sedative (SRsed) intoxication components. Another PCA created one component reflective of self-administered alcohol exposure (AE) over 90 min. Component loadings were entered as regressors in a voxel-wise general linear fMRI model, with reward type as a fixed factor. By design, peak prime breath alcohol concentration was similar across participants (29 ± 3.4 mg%). SRenjoy on the prime's ascending limb correlated positively with [SucroseHigh > Water] in the supplementary motor area and right dorsal anterior insula, implicating the salience network. Neither SR component correlated with the brain's response to MID. AE was unrelated to brain reward activation. While these findings do not support a relationship between alcohol self-administration and (1) subjective liking of or (2) regional brain response to an intensely sweet taste, they show that alcohol's enjoyable intoxicating effects on the rising limb correspond with anterior insular and supplementary motor area responses to high-concentration sucrose taste. No such associations were observed with MID despite robust activation in those regions. Insula and supplementary motor area responses to intense sensations relate to a known risk factor for AUD in a way that is not apparent with a secondary (monetary) reward.
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    Intoxication Effects on Impulsive Alcohol Choice in Heavy Drinkers; Correlation with Sensation Seeking and Differential Effects by Commodity
    (Wiley, 2021) Oberlin, Brandon G.; Carron, Claire R.; Ramer, Nolan E.; Plawecki, Martin H.; O’Connor, Sean J.; Kareken, David A.; Psychiatry, School of Medicine
    Background: The preference for immediate rewards and high sensation seeking are both potent risk factors for alcohol use disorder (AUD), but how they interact during intoxication is poorly understood. To model decision making linked to AUD risk, we tested heavy drinkers for impulsive choice (delay discounting with alcohol:money or money:money) and behavioral sensation seeking using a novel odor choice task. Laboratory tasks measured actual behavior with real contingencies. Our goals were to determine, in heavy drinkers, (i) alcohol's effects on delay discounting, and (ii) how AUD risk factors relate to delay discounting, and (iii) how delay discounting with alcohol choices compares with strictly monetary choices. Methods: Thirty-five heavy drinkers (≥2 binges per month; age = 22.8 ± 2.2; 20 male; 5.8 ± 2.3 drinks/drinking day) performed cross-commodity discounting (CCD) of immediate alcohol vs. delayed money, a monetary delay discounting (DD), and behavioral sensation-seeking tasks. CCD and DD were performed while sober and during controlled alcohol infusion targeting 0.08 g/dl. The behavioral sensation-seeking task presented binary choices of odorants varying in intensity and novelty, and the risk of exposure to a malodorant. Results: CCD and DD behaviors were highly correlated across conditions, mean r = 0.64. Alcohol increased delayed reward preference in DD, p = 0.001, but did not alter mean CCD, p > 0.16. However, alcohol-induced changes in CCD correlated with behavioral sensation seeking, such that higher sensation seekers' immediate alcohol preference increased when intoxicated, p = 0.042; self-reported sensation seeking was uncorrelated, ps > 0.08. Behavioral sensation seeking also correlated with "want" alcohol following a priming dose targeting 0.035 g/dl, p = 0.021. CCD and DD did not correlate with self-reported drinking problems or other personality risk traits. Conclusions: Alcohol increased impulsive alcohol choice in high sensation seekers, suggesting an interaction that may underlie impaired control of drinking, at least in a subset of heavy drinkers-consistent with models highlighting high novelty/sensation-seeking AUD subtypes. Discounting behavior overall appears to be a generalized process, and relatively stable across methods, repeated testing, and intoxication. These findings further support the utility of behavioral tasks in uncovering key behavioral phenotypes in AUD.
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    Pairing Neutral Cues with Alcohol Intoxication: New Findings in Executive and Attention Networks
    (Springer, 2018-09) Oberlin, Brandon G.; Dzemidzic, Mario; Eiler, William J.A.; Carron, Claire R.; Soeurt, Christina M.; Plawecki, Martin H.; Grahame, Nicholas J.; O’Connor, Sean J.; Kareken, David A.; Psychiatry, School of Medicine
    Rationale: Alcohol-associated stimuli capture attention, yet drinkers differ in the precise stimuli that become paired with intoxication. Objectives: Extending our prior work to examine the influence of alcoholism risk factors, we paired abstract visual stimuli with intravenous alcohol delivered covertly and examined brain responses to these Pavlovian conditioned stimuli in fMRI when subjects were not intoxicated. Methods: Sixty healthy drinkers performed task-irrelevant alcohol conditioning that presented geometric shapes as conditioned stimuli. Shapes were paired with a rapidly rising alcohol limb (CS+) using intravenous alcohol infusion targeting a final peak breath alcohol concentration of 0.045 g/dL or saline (CS−) infusion at matched rates. On day two, subjects performed monetary delay discounting outside the scanner to assess delay tolerance and then underwent event-related fMRI while performing the same task with CS+, CS−, and an irrelevant symbol. Results: CS+ elicited stronger activation than CS− in frontoparietal executive/attention and orbitofrontal reward-associated networks. Risk factors including family history, recent drinking, sex, and age of drinking onset did not relate to the [CS+ > CS−] activation. Delay-tolerant choice and [CS+ > CS−] activation in right inferior parietal cortex were positively related. Conclusions: Networks governing executive attention and reward showed enhanced responses to stimuli experimentally paired with intoxication, with the right parietal cortex implicated in both alcohol cue pairing and intertemporal choice. While different from our previous study results in 14 men, we believe this paradigm in a large sample of male and female drinkers offers novel insights into Pavlovian processes less affected by idiosyncratic drug associations.
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    Reliability of Striatal [11C]Raclopride Binding in Smokers Wearing Transdermal Nicotine Patches
    (Springer, 2012-02) Yoder, Karmen K.; Albrecht, Daniel S.; Kareken, David A.; Federici, Lauren M.; Perry, Kevin M.; Patton, Elizabeth A.; Zheng, Qi-Huang; Mock, Bruce H.; O’Connor, Sean J.; Herring, Christine M.; Department of Medicine, IU School of Medicine
    PURPOSE: In studies where [(11)C]raclopride (RAC) positron emission tomography (PET) is used to assess changes in striatal dopamine, it is important to control for cognitive states, such as drug craving, that could alter dopamine levels. In cigarette smokers, transdermal nicotine patches (TNP) can control nicotine craving, but the effects of nicotine patches on RAC binding are unknown. Thus, we sought to determine the test-retest reliability of RAC binding in the presence of nicotine patches. METHODS: Eleven male smokers were scanned twice with RAC on separate days while wearing TNP. RESULTS: Across the striatum, test-retest variability was 7.63 ± 5.88; percent change in binding potential was 1.11 ± 9.83; and the intraclass correlation coefficient was 0.91 (p < 0.0001). CONCLUSION: Baseline RAC binding is highly reproducible in smokers wearing nicotine patches. This suggests that TNP are an acceptable method for controlling cigarette craving during studies that utilize RAC to examine changes in dopamine.
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    Subjective Responses to Alcohol in the Development and Maintenance of Alcohol Use Disorder
    (American Psychiatric Association, 2021) King, Andrea; Vena, Ashley; Hasin, Deborah; deWit, Harriet; O’Connor, Sean J.; Cao, Dingcai; Psychiatry, School of Medicine
    Objective: Alcohol use disorder (AUD) remains an urgent public health problem. Longitudinal data are needed to clarify the role of acute subjective responses to alcohol in the development and maintenance of excessive drinking and AUD. The authors report on 10 years of repeated examination of acute alcohol responses in the Chicago Social Drinking Project. Methods: Young adult drinkers (N=190) participated in an initial alcohol challenge (0.8 g/kg of alcohol compared with placebo) that was repeated 5 and 10 years later. They were also assessed on drinking behavior and AUD symptoms at numerous intervals across the decade. Retention was high, as 184 of the 185 (99%) nondeceased active participants completed the 10-year follow-up, and 91% (163 of 179) of those eligible for alcohol consumption engaged in repeated laboratory testing during this interval. Results: At the end of the decade, 21% of participants met criteria for past-year AUD. Individuals who reported the greatest alcohol stimulation, liking, and wanting at the initial alcohol challenge were most likely to have developed AUD 10 years later. Further, alcohol-induced stimulation and wanting increased in reexamination testing among those with the highest AUD symptoms as the decade progressed. Conclusions: Initial stimulant and rewarding effects of alcohol predicted heavy alcohol use, and the magnitude of these positive subjective effects increased over a 10-year period in those who developed AUD compared with those who did not develop the disorder. The findings demonstrate systematic changes in subjective responses to alcohol over time, providing an empirical basis for prevention, early intervention, and treatment strategies.
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    To Infuse or Ingest in Human Laboratory Alcohol Research
    (Wiley, 2020-04) Cyders, Melissa A.; Plawecki, Martin H.; Corbin, William; King, Andrea; McCarthy, Denis M.; Ramchandani, Vijay A.; Weafer, Jessica; O’Connor, Sean J.; Psychology, School of Science
    Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper is to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, “To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs.” We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common, and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants’ brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes.