Browsing by Subject "alcoholism"

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    Adolescent and Adult Two-Bottle Choice Ethanol Drinking and Adult Impulsivity in Genetically Selected High-Alcohol Preferring Mice
    (2012-09-20) O'Tousa, David Scott; Grahame, Nicholas J.; Czachowski, Cristine; Boehm II, Stephen L.
    Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may be an inherent underlying biological process that precedes the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population, and assessed its effects on adult drinking and adult impulsivity. Experiment 1: Selectively bred High-Alcohol Preferring (HAP II) mice, which are shown to be highly impulsive, were given either alcohol (free choice access) or water only for two weeks during middle adolescence or adulthood. All mice were given free choice access to alcohol following 30 days without access, in adulthood. Experiment 2: Adolescent HAP II mice drank alcohol and water, or water alone, for two weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. Adolescent mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl in Experiment 1 and 108 mg/dl in Experiment 2. Adult mice reached average BECs of 154 mg/dl in Experiment 2. Mice pre-exposed to alcohol in either adolescence or adulthood showed a transient increase in ethanol consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. These findings indicate that HAP II mice drink intoxicating levels of alcohol during both adolescence and adulthood, and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity. Importantly, this research demonstrates that the HAP II mouse is a good candidate for a model of heavy adolescent alcohol consumption.
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    Association of structural brain imaging markers with alcoholism incorporating structural connectivity information: a regularized statistical approach
    (Office of the Vice Chancellor for Research, 2016-04-08) Karas, Marta; Dzemidzic, Mario; Goñi, Joaquin; Kareken, David A.; Harezlak, Jaroslaw
    Abstract: Brain imaging studies collect multiple imaging data types, but most analyses are done for each modality separately. Statistical methods that simultaneously utilize and combine multiple data types can instead provide a more holistic view of brain function. Here we model associations between alcohol abuse phenotypes and imaging data while incorporating prior scientific knowledge. Specifically, we utilize cortical thickness and integrated rectified mean curvature measures obtained by FreeSurfer software [1] to predict the alcoholism-related phenotypes while incorporating prior information from the structural connectivity between cortical regions. The sample consisted of 148 young (21-35 years) social-to-heavy drinking male subjects from several alcoholism risk studies [2,3,4]. Structural connectivity model [5] was used to estimate the density of connections between 66 cortical regions based on Desikan-Killiany atlas [6]. We employed a functional linear model with a penalty operator to quantify the relative contributions of imaging markers obtained from high resolution structural MRI (cortical thickness and curvature) as predictors of drinking frequency and risk-relevant personality traits, while co-varying for age. Model parameters were estimated by a unified approach directly incorporating structural connectivity information into the estimation by exploiting the joint eigenproperties of the predictors and the penalty operator [7]. We found that the best predictive imaging markers of the Alcohol Use Disorders Identification Test (AUDIT) score were the average thickness of left frontal pole (-), right transverse temporal gyrus (+), left inferior parietal lobule (+), right supramarginal gyrus (-), right rostral middle frontal gyrus (+), right precentral gyrus (+), left superior parietal lobule (-), left lateral orbitofrontal cortex (+), left rostral middle frontal gyrus (+), left postcentral gyrus (+) and left supramarginal gyrus (-), where (+) denotes positive and (-) negative association. In summary, the use of structural connectivity information allowed the incorporation of different modalities in associating cortical measures and alcoholism risk.
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    A common molecular mechanism for cognitive deficits and craving in alcoholism
    (Cold Spring Harbor Laboratory Press, 2020) Meinhardt, Marcus W.; Pfarr, Simone; Rohleder, Cathrin; Vengeliene, Valentina; Barroso-Flores, Janet; Hoffmann, Rebecca; Meinhardt, Manuela L.; Paul, Elisabeth; Hansson, Anita C.; Köhr, Georg; Meier, Nils; von Bohlen und Halbach, Oliver; Bell, Richard L.; Endepols, Heike; Neumaier, Bernd; Schönig, Kai; Bartsch, Dusan; Spanagel, Rainer; Sommer, Wolfgang H.; Psychiatry, School of Medicine
    Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.
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    Delay discounting and alcohol consumption correlate with dorsal anterior insula activation during choice in non‐treatment‐seeking heavy drinkers
    (Wiley, 2022) Halcomb, Meredith; Dzemidzic, Mario; Shen, Yitong I.; Lin, Zikai; Butcher, Tarah J.; Yoder, Karmen K.; Oberlin, Brandon; Radiology and Imaging Sciences, School of Medicine
    Background The anterior insular cortex (AIC), a prominent salience network node, integrates interoceptive information and emotional states into decision-making. While AIC activation during delay discounting (DD) in alcohol use disorder (AUD) has been previously reported, the associations between AIC activation, impulsive choice, alcohol consumption, and connectivity remain unknown. We therefore tested AIC brain responses during DD in heavy drinkers and their association with DD performance, alcohol drinking, and task-based connectivity. Methods Twenty-nine heavy drinkers (12 females; 31.5±6.1 years; 40.8±23.4 drinks/week) completed a DD task during functional MRI. Regions activated during delay discounting decision-making were tested for correlations with DD behavior and alcohol drinking. Psychophysiological interaction (PPI) models assessed task-dependent functional connectivity (FC) of activation during choice. Results DD choice activated bilateral anterior insular cortex, anterior cingulate cortex, and left precentral gyrus. Right dorsal (d) AIC activation during choice negatively correlated with discounting of delayed rewards and alcohol consumption. PPI analysis revealed FC of right dAIC to both anterior and posterior cingulate cortex (PCC)—key nodes in the midline default mode network. Conclusions Greater dAIC involvement in intertemporal choice may confer more adaptive behavior (lower impulsivity and alcohol consumption). Moreover, salience network processes governing discounting may require midline default mode (precuneus/PCC) recruitment. These findings support a key adaptive role for right dAIC in decision-making involving future rewards and risky drinking.
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    Development of Cross-Tolerance Between Ethanol and Baclofen in C57Bl/6J Mice
    (Office of the Vice Chancellor for Research, 2014-04-11) Blasingame, Shelby N.; Kasten, Chelsea R.; Boehm, Stephen L., II
    Alcohol is one of the most commonly used drugs of abuse. One criteria of alcohol abuse is the development of tolerance, meaning that more of the substance has to be ingested to produce the same pharmacological or behavioral effects. The phenomenon of cross-tolerance is when use of one substance leads to tolerance to an unused substance. Ethanol has also been shown to produce cross-tolerance to other drugs, such as benzodiazepines. The purpose of the current study was to investigate whether prior binge-like ethanol exposure in C57Bl/6J (B6) mice would produce a cross-tolerance to the locomotor sedative effects of the GABAB agonist R(+)-baclofen. We exposed 32 B6 male mice to a limited-access binge-like drinking procedure. Mice received daily access to either 0.2% saccharin or 20% ethanol for 2 hours, 3 hours into the dark cycle each day. There were four groups; 5 days of saccharin or ethanol access, and 10 days of saccharin or ethanol access. Baseline locomotor recordings were taken before ethanol drinking using Versamax activity monitors. Twenty-two hours following the last day of binge-like ethanol access, all animals received a 10mg/kg injection of R(+)-baclofen and Versamax activity was recorded for 1 hour. Sedation scores were calculated by subtracting the challenge day locomotor scores from the baseline locomotor scores. There was no effect of length of exposure (5 versus 10 days) or fluid type (ethanol versus saccharin) on total sedation scores (p<.05). A Length of Exposure*Fluid Type*Time-Bin ANOVA looking at sedation scores in 5 minute bins revealed a trend towards an omnibus interaction, but it did not reach significance (p=0.64). There was a main effect of time, with sedation scores being lower immediately following the injection (9<.05). These results indicate that ethanol does not produce a locomotors cross-tolerance to R(+)-baclofen.
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    Different Lines of Rats Selectively-Bred for High Alcohol-Drinking Demonstrate Disparate Preferences for Nicotine Self-administration
    (Ashdin, 2016-05) Rezvani, Amir H.; Levin, Edward D.; Wells, Corinne; Slade, Susan; Morrison, Margaret; Marshall, Lindsey; Morris, Matt; Confino, Jamie; Allenby, Cheyenne; Lumeng, Lawrence; Department of Medicine, IU School of Medicine
    Background. Alcohol and nicotine are commonly co-abused. The search for a common core of neural, behavioral, and genetic factors underlying addiction has been the goal of addiction research. Purpose. Genetic predisposition to high alcohol intake has been studied in rats by selectively breeding rats that have high preference for alcohol. The current experiments were conducted to determine if the level of intravenous nicotine administration for the various lines of alcohol-preferring rats differs from that for nonalcohol-preferring controls. Study design. Adult alcohol-naïve selectively-bred alcohol-preferring male rats from four lines (P, AA, HAD-1, sP) and their control nonalcohol-preferring rats (NP, ANA, LAD-1, sNP) were trained and given access to self-administer nicotine (0.03 mg/kg/infusion). Results. The results show that the P rats self-administered significantly more nicotine than NP rats. In contrast, there were no significant differences in nicotine self-administration between the sP and sNP or the AA and ANA rats. Unexpectedly, high alcohol-drinking HAD-1 rats self-administered significantly less nicotine than low alcohol-drinking LAD-1 rats. Conclusion. This suggests that some genetic factors that underlie high-alcohol intake have more general effects in promoting high nicotine intake tendencies, while other genetic factors are more specific to only heavy drinking.
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    Effects of Intoxicating Free-Choice Alcohol Consumption During Adolescence on Drinking and Impulsivity During Adulthood in Selectively Bred High Alcohol Preferring Mice
    (Wiley, 2013-01) O’Tousa, David Scott; Matson, Liana Marie; Grahame, Nicholas Joseph; Department of Psychology, School of Science
    Background— Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may precede the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population, and assessed its effects on adult drinking and adult impulsivity. Methods— Experiment 1: Selectively bred High-Alcohol Preferring (HAPII) mice were given either alcohol (free choice access) or water only for two weeks during middle adolescence or adulthood. All mice were given free choice access to alcohol 30 days later, in adulthood. Experiment 2: Adolescent HAPII mice drank alcohol and water, or water alone, for two weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. Results— Mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl (adolescent) or 154 mg/dl (adult) in Experiment 1. Adolescent mice in experiment 2 reached an average of 108 mg/dl. Mice exposed to alcohol in either adolescence or adulthood showed a transient increase in ethanol consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. Conclusions— These findings indicate that HAPII mice drink intoxicating levels of alcohol during both adolescence and adulthood, and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity.
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    Effects of the Selective PDE4B Inhibitor TDP-003 on Ethanol Consumption
    (Office of the Vice Chancellor for Research, 2014-04-11) Despard, Jessica Lee; Grahame, Nicholas; Halcomb, Meredith
    Alcoholism is a disease that affects about 18 million Americans. Inhibition of drinking behavior can help develop better therapeutic and medical treatments to these people. Phosphodiesterase-4 (PDE4) is an enzyme that helps breakdown cAMP, which in turn decrease alcohol consumption. cHAP mice are known to have a unique strong preference to ethanol. However, it is not yet known whether or not this relatively new strain of mice are affected by known agonists and antagonist neurotransmitters that reduce ethanol consumption in cousin strains. cHAP mice were used in this particular study due to their unique genetic make-up of having an above average preference to ethanol. The mice were trained for ethanol preference for two weeks. Once the cHAPs obtained stable ethanol consumption, the drug TDP-003, which contains the PDE4B subtype inhibitor, was administered in the morning with interval ethanol and water consumption readings every two hours from the time of injection. TDP-003 was given in three separate doses; 0.03ml, 0.1ml, and a 0.3ml mg/k along with a vehicle dose, which served as a control. Once data was collected and analyzed, it was found that there was not a significant effect in the amount of ethanol the cHAPs were consuming with the drug. In order to ensure that this result was not due to an experimental methods design error, the cHAPs were ran for another week on stable ethanol consumption and then injected with rolipram to see if a positive effect occurred. Rolipram is also a PDE4 inhibitor; predominantly affecting the PDE4B subtype. cHAPS were given three separate doses of rolipram, a 0.1ml, 0.25ml, and a 0.5ml mg/k dose, along with a vehicle dose. Once again, there were no significant differences in the amount of ethanol consumption that was consumed; thus implying that TDP-003 did not work.
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    AN EXAMINATION OF DEVELOPMENTAL AND SEX DIFFERENCES IN ETHANOL CONSUMPTION BY LOW ALCOHOL-CONSUMING RAT LINES
    (Office of the Vice Chancellor for Research, 2012-04-13) Largent, Tammie Rachell; Neal-Beliveau, Bethany S.; Bell, Richard L.
    In the United States, alcohol use and dependence is a major health issue affecting 4-5% of the population (Hasin et al., 2007). Research indicates ad-olescents ages 12-20 drink 11% of all alcohol consumed nationally, with more than 90% consumed in the form of binge drinking (Center for Disease Control and Prevention, 2010). Similar to the human condition, adolescent rodents generally consume more ethanol than their adult counterparts. Current rat animal model studies on alcoholism remain weighted toward examining Family History Positive (FHP), selectively bred, alcohol-preferring lines. Also, research has generally been focused on ethanol consumption be-havior of male rodents. However, female rodents tend to consume more al-cohol than male rodents (e.g., Adams et al., 1991). In addition, existing re-search on adolescent vs. adult alcohol abuse using “FHP” rats is not paral-leled by research with “Family History Negative” (FHN) rats, which might re-veal factors that prevent/protect an individual from excessive ethanol intake during this crucial stage of development. The purpose of this study was to evaluate ethanol consumption by male and female FHN, selectively bred, alcohol-nonpreferring rats during adoles-cence and adulthood. Studying adolescent vs. adult behavior may reveal de-velopmentally-specific, protective factors. Also, examining male versus fe-male behavior may reveal sex-by-development factors guarding against al-cohol abuse. Animals were placed in cages and assigned to experimental conditions defined by the following independent variables: line of rodent, rodent’s sex and age of ethanol exposure. The following dependent measures were exam-ined: changes in body weight as well as water and ethanol consumption. These measures were taken at least 5 days per week. We hypothesized that there would be elevated levels of ethanol con-sumption (g ethanol/kg body weight/day) in (a) adolescent vs. adult rats and (b) female vs. male rats. Future research might focus on gene and/or protein expression differences within certain nuclei of the brain’s reward neurocircuit between the FHP and FHN lines of rats. Currently, some data has been collected and statistically analyzed. Upon completion the study re-sults will be prepared for presentation and manuscript submission. Funded in part by the Indiana University-Purdue University Indianapolis, Undergraduate Re-search Opportunities Program (UROP)
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