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ItemAlterations in the rate of binge ethanol consumption: implications for preclinical studies in mice(Wiley Blackwell (Blackwell Publishing), 2014-09) Linsenbardt, David N.; Boehm, Stephen L.; Department of Psychology, IU School of ScienceThe rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies. ItemChronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms(American Society for Clinical Investigation, 2020-06-16) Ma, Jing; Cao, Haixia; Rodrigues, Robim M.; Xu, Mingjiang; Ren, Tianyi; He, Yong; Hwang, Seonghwan; Feng, Dechun; Ren, Ruixue; Yang, Peixin; Liangpunsakul, Suthat; Sun, Jian; Gao, Bin; Medicine, School of MedicineAlcohol-associated liver disease is a spectrum of liver disorders with histopathological changes ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recent data suggest that chronic-plus-binge ethanol intake induces steatohepatitis by promoting release by hepatocytes of proinflammatory mitochondrial DNA–enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal–regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol–induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (Mt1/2), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the Mt1 and Mt2 genes aggravated ethanol-induced liver injury, as evidenced by elevation of serum ALT, neutrophil infiltration, oxidative stress, and ASK1/p38 activation in the liver. Inhibition or genetic deletion of Ask1 or p38 ameliorated ethanol-induced liver injury, inflammation, ROS levels, and expression of phagocytic oxidase and ER stress markers in the liver. In addition, inhibition of ASK1 or p38 also attenuated ethanol-induced mtDNA-enriched EV secretion from hepatocytes. Taken together, these findings indicate that induction of hepatic mtDNA-enriched EVs by ethanol is dependent on ASK1 and p38, thereby promoting alcoholic steatohepatitis. ItemComputed tomography assessment of peripubertal craniofacial morphology in a sheep model of binge alcohol drinking in the first trimester(Elsevier, 2015-11) Birch, Sharla M.; Lenox, Mark W.; Kornegay, Joe N.; Shen, Li; Ai, Huisi; Ren, Xiaowei; Goodlett, Charles R.; Cudd, Tim A.; Washburn, Shannon E.; Department of Medical & Molecular Genetics, IU School of MedicineIdentification of facial dysmorphology is essential for the diagnosis of fetal alcohol syndrome (FAS); however, most children with fetal alcohol spectrum disorders (FASD) do not meet the dysmorphology criterion. Additional objective indicators are needed to help identify the broader spectrum of children affected by prenatal alcohol exposure. Computed tomography (CT) was used in a sheep model of prenatal binge alcohol exposure to test the hypothesis that quantitative measures of craniofacial bone volumes and linear distances could identify alcohol-exposed lambs. Pregnant sheep were randomly assigned to four groups: heavy binge alcohol, 2.5 g/kg/day (HBA); binge alcohol, 1.75 g/kg/day (BA); saline control (SC); and normal control (NC). Intravenous alcohol (BA; HBA) or saline (SC) infusions were given three consecutive days per week from gestation day 4-41, and a CT scan was performed on postnatal day 182. The volumes of eight skull bones, cranial circumference, and 19 linear measures of the face and skull were compared among treatment groups. Lambs from both alcohol groups showed significant reduction in seven of the eight skull bones and total skull bone volume, as well as cranial circumference. Alcohol exposure also decreased four of the 19 craniofacial measures. Discriminant analysis showed that alcohol-exposed and control lambs could be classified with high accuracy based on total skull bone volume, frontal, parietal, or mandibular bone volumes, cranial circumference, or interorbital distance. Total skull volume was significantly more sensitive than cranial circumference in identifying the alcohol-exposed lambs when alcohol-exposed lambs were classified using the typical FAS diagnostic cutoff of ≤10th percentile. This first demonstration of the usefulness of CT-derived craniofacial measures in a sheep model of FASD following binge-like alcohol exposure during the first trimester suggests that volumetric measurement of cranial bones may be a novel biomarker for binge alcohol exposure during the first trimester to help identify non-dysmorphic children with FASD. ItemDoes a Crossover Age Effect Exist for African American and Hispanic Binge Drinkers? Findings from the 2010 to 2013 National Study on Drug Use and Health(Wiley, 2017-06) Zapolski, Tamika C. B.; Baldwin, Patrick; Banks, Devin E.; Stump, Timothy E.; Psychology, School of ScienceBACKGROUND: Among general population studies, lower rates of binge drinking tend to be found among African Americans and Hispanics compared to Whites. However, among older adult populations, minority groups have been shown to be at higher risk for binge drinking, suggesting the presence of a crossover effect from low to high risk as a function of age. To date, limited research has examined the crossover effect among African American and Hispanic populations compared to non-Hispanic Whites across large developmental time frames or explored variation in risk based on income or gender. This study aimed to fill these gaps in the literature. METHODS: Data were compiled from the 2010 to 2013 National Survey on Drug Use and Health surveys, which provide annual, nationally representative data on substance use behaviors among individuals aged 12 and older. Hispanic, non-Hispanic African American, and non-Hispanic White respondents were included (N = 205,198) in the analyses. RESULTS: A crossover effect was found for African American males and females among the lowest income level (i.e., incomes less than $20,000). Specifically, after controlling for education and marital status, compared to Whites, risk for binge drinking was lower for African American males at ages 18 to 24 and for females at ages 18 to 34, but higher for both African American males and females at ages 50 to 64. No crossover effect was found for Hispanic respondents. CONCLUSIONS: Although African Americans are generally at lower risk for binge drinking, risk appears to increase disproportionately with age among those who are impoverished. Explanatory factors, such as social determinants of health prevalent within low-income African American communities (e.g., lower education, violence exposure, housing insecurity) and potential areas for intervention programming are discussed. ItemThe effect of voluntary binge caffeine and ethanol co-exposure on neurobehavioral sensitivity to cocaine in male C57BL/6J mice(2016-05) Fritz, Brandon M.; Boehm, Stephen L., II; Czachowski, Cristine Lynn; Kinzig, Kimberly; Engleman, Eric A.; Grahame, Nicholas J.Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use. ItemInvestigating the role of extrasynaptic GABAA receptors located in the infralimbic cortex in the binge-like alcohol intake of male C57BL/6J mice(2013-11-20) Fritz, Brandon Michael; Boehm, Stephen; Czachowsk, Cristine; Grahame, Nicholas J.Extrasynaptic GABAA receptors, often identified as those containing both α4 and δ subunits, appear to be a target for the actions of alcohol (ethanol) at relatively low concentrations, perhaps suppressing the activity of GABAergic interneurons which regulate activity in the mesolimbocortical circuit. Pharmacological studies in rodents using the δ-subunit selective agonist Gaboxadol (THIP) have found both promotional and inhibitory effects on alcohol consumption. The goal of this project was to determine the role of extrasynaptic GABAA receptors located in the infralimbic cortex (ILC) in the binge-like alcohol intake of male C57BL/6J (B6) mice. The ILC is of interest due to its demonstrated involvement in stress reactivity and alcohol exposure has been shown to interfere with extinction learning; impairments of which may be related to inflexible behavior (i.e. problematic alcohol consumption). Adult male B6 mice were bilaterally implanted with stainless steel guide cannulae aimed at the ILC and were offered limited access to 20% ethanol or 5% sucrose for 6 days. On day 7, mice were bilaterally injected with 50 or 100 ng THIP (25 or 50 ng per side respectively) or saline vehicle into the ILC. It was found that the highest dose of THIP (100 ng/mouse) increased alcohol intake relative to vehicle controls, although control animals consumed relatively little ethanol following infusion. Furthermore, THIP had no effect on sucrose consumption (p > 0.05), suggesting that the effect of THIP was selective for ethanol consumption. Together, these findings suggest that the mice that consumed ethanol may have been particularly reactive to the microinfusion process relative to animals that consumed sucrose, perhaps because ethanol consumption was not as reinforcing as sucrose consumption. In addition, the observation that THIP effectively prevented the decrease in ethanol intake on day 7 induced by the microinjection process may be related to a role for the ILC in adaptive learning processes, which in turn, promote behavioral flexibility. ItemLeveraging Whole Brain Imaging to Identify Brain Regions Involved in Alcohol Frontloading(2023-12) Ardinger, Cherish; Lapish, Christopher; Grahame, Nicholas; Czachowski, Cristine; Kimbrough, AdamFrontloading is an alcohol drinking pattern where intake is skewed toward the onset of access. The goal of the current study was to identify brain regions involved in frontloading using whole brain imaging. 63 C57Bl/6J (32 female and 31 male) mice underwent 8 days of binge drinking using drinking-in-the-dark (DID). Three hours into the dark cycle, mice received 20% (v/v) alcohol or water for two hours on days 1-7. Intake was measured in 1-minute bins using volumetric sippers, which facilitated analyses of drinking patterns. Mice were perfused 80 minutes into the day 8 DID session and brains were extracted and processed for iDISCO clearing and c-fos immunohistochemistry. For brain network analyses, day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a change-point analysis described in our recent ACER publication (Ardinger et al., 2022). Groups were female frontloaders (n = 20), female non-frontloaders (n = 2), male frontloaders (n = 13) and male non-frontloaders (n = 8). There were no differences in total alcohol intake as a function of frontloading status. Water drinkers had an n of 10 for each sex. As only two female mice were characterized as non-frontloaders, it was not possible to construct a functional correlation network for this group. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect fos+ cells. Functional correlation matrices were calculated for each group from log10 c-fos values. Euclidean distances were calculated from these R values and hierarchical clustering was used to determine modules (highly connected groups of brain regions) at a tree-cut height of 50%. In males, alcohol access decreased modularity (3 modules in both frontloaders and non-frontloaders) as compared to water drinkers (7 modules). In females, an opposite effect was observed. Alcohol access (9 modules) increased modularity as compared to water drinkers (5 modules). These results suggest sex differences in how alcohol consumption reorganizes the functional architecture of networks. Next, key brain regions in each network were identified. Connector hubs, which primarily facilitate communication between modules, and provincial hubs, which facilitate communication within modules, were of specific interest for their important and differing roles. In males, 4 connector hubs and 17 provincial hubs were uniquely identified in frontloaders (i.e., were brain regions that did not have this status in male non-frontloaders or water drinkers). These represented a group of hindbrain regions (e.g., locus coeruleus and the pontine gray) connected to striatal/cortical regions (e.g., cortical amygdalar area) by the paraventricular nucleus of the thalamus. In females, 16 connector and 17 provincial hubs were uniquely identified which were distributed across 8 of the 9 modules in the female alcohol drinker network. Only one brain region (the nucleus raphe pontis) was a connector hub in both sexes, suggesting that frontloading in males and females may be driven by different brain regions. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females, and recruited different hub brain regions between the sexes. These results suggest target brain regions for future studies to try to manipulate frontloading behavior and more broadly contribute to the literature on alcohol’s effect on neural networks. Item"Wired," yet intoxicated: modeling binge caffeine and alcohol co-consumption in the mouse(Wiley Blackwell (Blackwell Publishing), 2014-08) Fritz, Brandon M.; Companion, Michel; Boehm, Stephen L.; Department of Psychology, IU School of ScienceBACKGROUND: The combination of highly caffeinated "energy drinks" with alcohol (ethanol [EtOH]) has become popular among young adults and intoxication via such beverages has been associated with an elevated risk for harmful behaviors. However, there are discrepancies in the human literature regarding the effect of caffeine on alcohol intoxication, perhaps due to confounding factors such as personality type, expectancy, and history of exposure. Animal models of co-exposure are resistant to such issues; however, the consequences of voluntary co-consumption have been largely ignored in the animal literature. The primary goal of this work was to characterize a mouse model of binge caffeine and EtOH co-consumption employing the limited access "Drinking-in-the-Dark" (DID) paradigm. METHODS: Caffeine was added to a 20% alcohol solution via DID. Alcohol/caffeine intake, locomotor behavior, ataxia, anxiety-like behavior, and cognitive function were evaluated as a consequence of co-consumption in adult male C57BL/6J mice. RESULTS: Caffeine did not substantially alter binge alcohol intake or resultant blood EtOH concentrations (BECs), nor did it alter alcohol's anxiolytic effects on the elevated plus maze or cognitive-interfering effects in a novel object-recognition task. However, no evidence of alcohol-induced sedation was observed in co-consumption groups that instead demonstrated a highly stimulated state similar to that of caffeine alone. The addition of caffeine was also found to mitigate alcohol-induced ataxia. CONCLUSIONS: Taken together, our mouse model indicates that binge co-consumption of caffeine and alcohol produces a stimulated, less ataxic and anxious, as well as cognitively altered state; a state that could be of great public health concern. These results appear to resemble the colloquially identified "wide awake drunk" state that individuals seek via consumption of such beverages. This self-administration model therefore offers the capacity for translationally valid explorations of the neurobiological consequences of binge co-consumption to assess the public health risk of this drug combination.