Browsing by Author "Carron, Claire R."
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Item Assessing Motivational and Associative Learning Mechanisms Underlying Compulsive Drinking(2021-08) Carron, Claire R.; Grahame, Nicholas; Czachowski, Cristine; Lapish, Christopher; Hopf, FredricContinued consumption of alcohol despite the knowledge of negative consequences is a hallmark of alcohol use disorder (AUD), yet much remains unknown about what motivates these behaviors. Compulsive drinking may require motivational resources that are not necessary when drinking in unchallenged conditions in order to counteract the addition of these negative consequences. Increased sensitivity to drug-paired stimuli via associative learning processes may provide this additional motivation. To evaluate if alcohol-paired stimuli enhance alcohol seeking, selectively bred crossed High Alcohol Preferring mice experienced Pavlovian conditioning procedures with an alcohol unconditioned stimulus. We hypothesized that after repeated pairings, alcohol cues would elicit seeking conditioned responses. Then, to determine if the motivation provided by these cues influenced responding, mice were trained to respond for alcohol and tested in the presence of alcohol cues. Finally, to test if alcohol-paired cues influence compulsive drinking, this same test was repeated with the addition of response-contingent footshock. We hypothesized the cue paired with alcohol would increase responding for alcohol in unchallenged conditions, but especially in challenged conditions, contributing to compulsivity. An auditory stimulus paired with alcohol did elicit enhanced seeking responses, but contrary to hypothesis, we observed no effect of these same cues on instrumental responding. To validate these findings, training and testing procedures must be optimized to ensure conditioning has properly occurred and compulsivity is being appropriately measured.Item The disengaging brain: Dynamic transitions from cognitive engagement and alcoholism risk(Elsevier, 2020-04) Amico, Enrico; Dzemidzic, Mario; Oberlin, Brandon G.; Carron, Claire R.; Harezlak, Jaroslaw; Goñi, Joaquín; Kareken, David A.; Neurology, School of MedicineHuman functional brain connectivity is usually measured either at “rest” or during cognitive tasks, ignoring life’s moments of mental transition. We propose a different approach to understanding brain network transitions. We applied a novel independent component analysis of functional connectivity during motor inhibition (stop signal task) and during the continuous transition to an immediately ensuing rest. A functional network reconfiguration process emerged that: (i) was most prominent in those without familial alcoholism risk, (ii) encompassed brain areas engaged by the task, yet (iii) appeared only transiently after task cessation. The pattern was not present in a pre-task rest scan or in the remaining minutes of post-task rest. Finally, this transient network reconfiguration related to a key behavioral trait of addiction risk: reward delay discounting. These novel findings illustrate how dynamic brain functional reconfiguration during normally unstudied periods of cognitive transition might reflect addiction vulnerability, and potentially other forms of brain dysfunction.Item Family history of alcoholism and the human brain response to oral sucrose(Elsevier, 2017-12-12) Eiler, William J.A., II; Dzemidzic, Mario; Soeurt, Christina M.; Carron, Claire R.; Oberlin, Brandon G.; Considine, Robert V.; Harezlak, Jaroslaw; Kareken, David A.; Neurology, School of MedicineA heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD) activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP) or negative (FHN) for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men) rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI) during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M). In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk.Item Innate and Acquired Quinine‐Resistant Alcohol, but not Saccharin, Drinking in Crossed High–Alcohol‐Preferring Mice(Wiley, 2019-11) Houck, Christa A.; Carron, Claire R.; Millie, Lauren A.; Grahame, Nicholas J.; Psychology, School of ScienceBackground Alcohol consumption despite aversive consequences is often a key component of an alcoholism diagnosis. Free‐choice alcohol consumption despite bitter quinine adulteration in rodents has been seen following several months of free‐choice drinking, but there has been little study of whether prolonged access to other palatable substances such as saccharin yields quinine resistance. Selectively bred crossed high–alcohol‐preferring (cHAP) mice average blood alcohol levels of over 250 mg/dl during free‐choice access, considerably higher than other models. We hypothesized that higher intakes would yield more rapid development of quinine‐resistant alcohol (QRA) drinking and quinine‐resistant saccharin (QRS) drinking. Methods All experiments used male and female cHAP mice. Experiment 1 compared mice with either 0 or 5 weeks of alcohol drinking history, testing varying (0.032, 0.10, 0.32 g/l) quinine concentrations in ethanol. Experiment 2 examined whether innate QR may exist, comparing animals with a 1 or zero day of drinking history. Experiment 3 examined the effect of varying histories (0, 2, or 5 weeks) of free‐choice 10% alcohol drinking on QR alcohol consumption at high quinine concentrations. Finally, Experiment 4 investigated the development of QRS drinking. Results We found that we could not detect a history effect in commonly used quinine concentrations, indicating that cHAP mice are innately quinine resistant to 0.10 g/l quinine. However, we were able to determine that a 2‐week drinking history was sufficient to induce QRA drinking in cHAP mice at extremely high quinine concentrations (0.74 and 0.32 g/l). However, the history effect was specific to QRA, a saccharin drinking history, did not yield QRS drinking. Conclusions These data suggest that an alcohol drinking history induces maladaptive behaviors, such as drinking in spite of negative consequences, a pattern not seen with saccharin. Furthermore, a strong genetic predisposition to drink may promote an innate aversion resistance compared with commonly used inbred strains.Item 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 MedicineBackground: 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.Item A Novel Risky Decision-Making Task in High and Low Alcohol Preferring Mice(2018-12) Carron, Claire R.; Grahame, Nicholas J.; Czachowski, Cristine L.; Lapish, Christopher C.Deficits in impulse control and decision-making have been implicated in the development and maintenance of alcohol use disorders (AUDs). Individuals with AUD often make disadvantageous choices under conditions of probabilistic risk. The Iowa Gambling Task (IGT) is often used to measure risky decision-making, in which impaired individuals tend to favor large, infrequent rewards even when punished for these choices, rather than smaller, safer, and more advantageous rewards. It remains poorly understood if these deficits are behaviors under genetic control and if ethanol intoxication may alter decision-making. High and Low Alcohol Preferring (HAP3 and LAP3, respectively) mice were trained on a novel gambling task to investigate these possible influences. In Experiment 1, HAP3s and LAP3s responded for a 0.1% saccharin solution, choosing between a risky and a safe option. Importantly, choosing the risky option was meant to be ultimately disadvantageous. In Experiment 2, these same HAP3 mice responded for saccharin or saccharin plus 10% ethanol. Contrary to hypothesis, LAP3s preferred the risky option more than HAP3s. Alcohol increased preference for the risky lever, but only in male mice. HAP3 preference for the safe lever may be explained by higher motivation to obtain sweet rewards, or higher overall avidity for responding. Ethanol-induced changes in male risk behavior may be explained by higher androgen levels, but further investigation is required. Similarly, continued research is necessary to optimize a risky decision-making task for both lines, and thus investigate possible genetic differences in risk acceptance that correlate with differences in alcohol intake.Item 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 MedicineRationale: 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.