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Indiana University-Purdue University Indianapolis (IUPUI) / Impulsivity is associated with addiction in many human studies. Delay discounting (DD) is often used to measure impulsive choice in humans and animals. In DD testing, a small immediate reward is pitted against a larger delayed reward, and relative preference is assessed. The relative contribution of ethanol to impulsivity in alcoholism is not well-understood, therefore I will test the hypothesis that ethanol exposure will increase impulsivity in High Alcohol Preferring (HAP) mice as measured in an adjusting amount DD task. Selectively bred HAP mice were exposed to ethanol and tested in DD in 3 different experiments. Experiment 1: ad lib homecage ethanol drinking for 21 days and 17 days were used to expose mice to ethanol. Additionally, mice were tested in DD while “currently drinking” vs. “abstinent”. In experiment 2, to achieve higher blood alcohol concentrations, mice were injected with 3.5 g/kg ethanol 8 times and tested before and after in DD. In both experiments 1 and 2, mice were tested at only 2 delays (0.5 sec and 10 sec), to maximize sensitivity to detect shifts in choice behavior. In experiment 3, mice responded for 8% ethanol or 0.01% saccharin at a full range of delays: 0, 1, 2, 4, and 8 sec. Experiment 1 did not reveal any impact of ethanol drinking on impulsivity. Experiment 2 revealed a strong trend of reduced impulsivity in the 10 sec delay group after ethanol injections. Experiment 3 revealed reduced impulsivity at the 8 sec delay in the group responding for ethanol, and also revealed a significant correlation between higher ethanol drinking and reduced impulsivity. These data were unexpected, and imply that the a priori hypothesis not only should be rejected, but that the opposite hypothesis may be true: ethanol decreases impulsivity, at least with high dose exposure and in responding for it as a reinforcer. This effect was similar to the effect observed in other studies with amphetamine, which consistently decreases impulsivity. Ethanol may have been exerting an amphetamine-like effect on impulsivity at the doses tested here. There is no evidence in the data generated in these studies that ethanol increases impulsivity.

Amongst the important social problems today in both rural and urban areas, is the condition of inebriety. Although considerable research has been conducted on the condition of alcoholism, little has been undertaken on the condition of inebriety. It is an observable fact that, while members of some ethnic groups who drink substantially and frequently become inebriated, members of other ethnic groups who also partake of alcoholic beverages in substantial quantities do not experience inebriety. This suggests that the culture of the ethnic group determines the group's drinking patterns to a large measure, and that drinking patterns may be such that they lead participants to the condition of inebriety. In this thesis, I have attempted to examine drinking patterns of three ethnic groups in relation to several aspects of their cultural background. I devised and tested five hypotheses which are relevant to attitudes towards drinking, reasons for drinking, settings and times of the day in which drinking occurs. I have attempted also to examine Indian and Italian drinking patterns to determine to what extent each group matches or differs from Anglo-Saxon drinking patterns. The study was made on a comparative basis, and field work was conducted amongst three ethnic groups in the Greater Vancouver area during the summer, fall and winter, 1967-1968. The three groups are the Coast Salish Indians of the Mission Reserve, Immigrant Italians and Anglo-Saxons of East Vancouver. Data on the problem briefly outlined above, were sought through interviews with thirty representatives of each group, as well as by observations of members of the ethnic groups in their social drinking establishments. Two key informants in each ethnic group, as well as several pertinent documentary sources, were also consulted. The available data collected in the study suggested that the proposed hypotheses were valid. There appears to be a close relationship between the cultural background of an ethnic group and its drinking patterns. However, it needs to be stated that there were many inadequacies and limitations in the reference literature used, basic premises and hypotheses proposed, and research techniques employed. Data also suggested that there was a high degree of similarity between Anglo-Saxon and Indian drinking patterns and a high degree of difference between Anglo-Saxon and Italian drinking patterns. Additional and enlightening information which the data suggested was that many of the cultural aspects of the Indian group, particularly, are in a marked stage of transition. / Arts, Faculty of / Anthropology, Department of / Graduate

The adverse health and safety consequences of excessive alcohol consumption are a leading problem around the world. Alcoholic beverages are a routine part of socializing in many societies. However, alcohol is also a significant contributor to worldwide morbidity, disability, and mortality. To lessen the harm produced by alcohol, governments have adopted different alcohol control policies. These control policies can be group into four basic strategies: deterrence, prevention, communications and outreach, and alcohol treatment. Among the prevention measures, restricting physical access to alcohol by limiting the alcohol outlets' density, raising the legal age to purchase alcohol, and reducing the affordability of alcohol through taxation have been extensively shown as cost-effective and feasible measures against alcohol-related harms. However, there are still topics related to the affordability of alcohol that have not been investigated. The role of promotional price practices at on-premises alcohol outlets on health and social outcomes, and the effects of policies enacted to prevent these practices on motor vehicle crashes remained an unexplored research topic. The main goals of this dissertation were to summarize evidence regarding the health effects of drink specials and to estimate the effects of policies restricting drink special practices as preventive tools for fatal motor vehicle crashes. Specifically, I summarized the research evidence of the effects of drink special practices on health and social outcomes (Aim 1). I examined the association between drink special laws and alcohol-related fatal motor vehicle crashes contrasting results for two methodological approaches, difference-in-difference-in-differences (Aim 2) and synthetic controls (Aim 3). This dissertation contains five chapters. The introduction in chapter one provides a background review of relevant literature that serves as the conceptual framework for this dissertation and an overview of chapters two, three, four, and five. The systematic review of the literature relevant to Aim 1 is presented in chapter two. This review included studies on the effects that drink specials and drink special laws have on alcohol consumption, binge drinking, and alcohol-related harms. Twelve studies examined the effect of drink specials in seven countries between 1978 and 2018. Consistent evidence supported associations between drink specials and increased alcohol consumption, heavy drinking, alcohol intoxication, and other alcohol-related outcomes. For aims 2 and 3, I examined 36-years of data from the U.S. Department of Transportation, Census Bureau, and NIH’s Alcohol Policy Information System and National Institute on Alcohol Abuse and Alcoholism from 1982 to 2017. In chapter three, I presented results from difference-in-difference-in-differences analyses of the effects of implementing six drink special laws on alcohol- and non-alcohol-related motor vehicle fatal crash rates in the United States (U.S.). I assessed exposure to implementation as any law, number of laws, and each law. Random effects generalized least squares regression models adjusted for the proportion of males in the state, youth involved in fatal crashes, gallons of ethanol per capita among the population age 21 years and older, and autonomy index were fitted across 24 treated and 18 non-treated states. Results revealed that the implementation of any drink special law was associated with reductions in overall and alcohol-related fatal crash rates compared to untreated states. Also, drink special laws mitigated incremental rates of non-alcohol related crashes among treated states with any drink special law compared to untreated states. In chapter four, I presented results from synthetic control analyses for single and multiple treated units. I assessed the association between drink special laws and alcohol-related fatal motor vehicle crashes and adjusted for the same covariates as in chapter three. Results in chapter four indicated that states treated with any drink special law reduced alcohol-related fatal crash rates only in years three, five, and ten post-implementation compared to the synthetic control trend. The effects of any drink special law were more consistent at different times in the post-implementation for reducing non-alcohol-related fatal crash rates than the synthetic control trend. Findings for the number of laws implemented and each drink special laws were mixed. Chapter five presents a synthesis and discussion of findings in chapters two, three, and four, as well as policy recommendations for stakeholders and future research.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol dehydrogenase (ADH) genes encode proteins that metabolize ethanol to acetaldehyde. Humans have seven ADH genes in a cluster. The hypothesis of this study was that by controlling the levels of ADH enzymes, cis-regulatory regions could affect the risk for alcoholism. The goal was thus to identify distal regulatory regions of ADHs. To achieve this, sequence conservation across 220 kb of the ADH cluster was examined. An enhancer (4E) was identified upstream of ADH4. In HepG2 human hepatoma cells, 4E increased the activity of an ADH4 basal promoter by 50-fold. 4E was cell specific, as no enhancer activity was detected in a human lung cell line, H1299. The enhancer activity was located in a 565 bp region (4E3). Four FOXA and one HNF-1A protein binding sites were shown to be functional in the 4E3 region. To test if this region could affect the risk for alcoholism, the effect of variations in 4E3 on enhancer activity was tested. Two variations had a significant effect on enhancer activity, decreasing the activity to 0.6-fold. A third variation had a small but significant effect. The effect of variations in the ADH1B proximal promoter was also tested. At SNP rs1229982, the C allele had 30% lower activity than the A allele. In addition to studying the regulatory regions of ADH genes, the effects of alcohol on liver-derived cells (HepG2) were also explored. Liver is the primary site of alcohol metabolism, and is highly vulnerable to injuries due to chronic alcohol abuse. To identify the effects of long term ethanol exposure on global gene expression and alternative splicing, HepG2 cells were cultured in 75 mM ethanol for nine days. Global gene expression changes and alternative splicing were measured using Affymetrix GeneChip® Human Exon 1.0 ST Arrays. At the level of gene expression, genes involved in stress response pathways, metabolic pathways (including carbohydrate and lipid metabolism) and chromatin regulation were affected. Alcohol effects were also observed on alternative transcript isoforms of some genes.

Indiana University-Purdue University Indianapolis (IUPUI) / The present study sought to identify the effects of chronic lithium administration on ethanol intakes in high alcohol-preferring (HAP) mice. Lithium is a well-established treatment for bipolar disorder and has demonstrated efficacy in reducing impulsivity, an endophenotype of the disease. Impulsivity is also a prominent trait of alcoholism. HAP mice display a preference for consuming substantial amounts of ethanol and exhibit abnormally high levels of impulsivity. Previous work has determined that chronic lithium exposure in HAP mice reduces their levels of impulsivity. The present study analyzed fluctuations in established intake patterns after lithium exposure and how pre-exposure to lithium would affect ethanol intake acquisition. The results showed an increase in ethanol intake and no change in preference for ethanol over water in lithium treated mice. There was an increase in overall total fluid consumption in these mice, likely resulting from polydipsic effects. There also appeared to be a potentiated lithium toxicity effect found in those mice pre-exposed to lithium. The conclusion was that lithium therapy does not decrease ethanol consumption in HAP mice.

Indiana University-Purdue University Indianapolis (IUPUI) / Our laboratory has previously identified the clock gene D-box Binding Protein (DBP) as a candidate gene for bipolar disorder and alcoholism using a Convergent Functional Genomics (CFG) approach. In subsequent work, we established mice with a homozygous deletion of DBP as a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. In the present study, we found that the omega-3 fatty acid, DHA, may have mood stabilizing capabilities in stressed DBP knockout mice, and reduces alcohol consumption in these mice as well as in the alcohol preferring (P) rats. Given their potential health benefits and their relative lack of negative side-effects, omega-3 fatty acids may become an important supplement for bipolar patients and co-morbid alcoholics, a potential that warrants continued research.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol related problems and abuse continue to be serious problems in the U.S. today affecting nearly 17.6 million Americans. Understanding of the specific genes and related behaviors associated with alcohol use may provide substantial preventative measures for those who are at an increased risk. Genetically selected lines such as the high-alcohol preferring (HAP) and low-alcohol preferring (LAP) mice have been created to examine which endophenotypes co-segregate with alcohol preference. One behavioral trait that has been commonly associated with alcohol related problems is impulsivity. Impulsivity is the inability to withhold a response (motor impulsivity) or to act without forethought (cognitive impulsivity). The latter comprises much of the research and literature today using delay discounting models to tease out differences in subject’s wiliness to discount larger reinforcers for smaller immediate reinforcers. This study utilized relatively two newer paradigms associated with motor impulsivity in attempt to test differences in response disinhibition between two independent replicate HAP and LAP lines. It is hypothesized that the genes responsible for alcohol preference would be genetically correlated with motor impulsivity as HAP mice would display a greater degree of response disinhibition. Two independent replicates consisting of 48 mice (24 HAP II and 24 LAP II, representing the 37th generation; 24 HAP III and 24 LAP III, representing the 13th generation) were tested in two separate identical experiments. Each experiment was comprised of three phases. Phase I utilized a fixed interval (FI) 120s procedure for 30 days. After the 30 days of FI exposure mice were immediately moved to phase II for 10 days which implored a differential reinforcement of low rate procedure (DRL) at a time interval of 20s. Phase III used the same procedures as Phase II except the DRL was increased to 32s. As hypothesized, there was a moderate genetic correlation between alcohol preference and impulsivity as the HAP II mice displayed greater response disinhibition throughout all three phases compared to the LAP II mice. No differences were observed amongst the replicate III mice in any of the three phases. The findings from this study provide additional support that a genetic correlation between alcohol preference and impulsivity exists as seen in the delay discounting literature. Though this was observed in only one of the two replicates, interpretations must be taken at caution as the replicate III mice are still in the early stages of selection. It is possible at this stage in the selection process that increases in alcohol over successive generations are associated with selecting for taste until a threshold is met where selection shifts to pharmacologic drinking relevance. Until later generations of replicate III mice are studied where pharmacologic drinking occurs, conclusions from this study provide a moderate genetic correlation between alcohol preference and impulsivity.

Indiana University-Purdue University Indianapolis (IUPUI) / 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.