Both genetic and environmental contributions have crucial roles in the development of a complex disease such as alcoholism. Unfortunately, little progress has been made in identifying the underlying molecular mechanisms altered during abstinence to aid development of novel therapeutics for the maintenance of sobriety. We propose a combined genetic, molecular, pharmacological and behavioral strategy to identify pathways that are altered after a period of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic alcohol abuse, but the stability of these expression differences in the abstinent alcoholic is controversial. We have previously reported identification of pathways altered in prefrontal cortex (PFC), a brain region associated with cognitive dysfunction and damage in alcoholics, during a defined period of abstinence. To characterize genetic contributions, both sexes of an animal model with widely divergent responses to alcohol derived by selective breeding, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines, were analyzed. During a sustained period of abstinence, the transcriptional response correlated with withdrawal phenotype rather than sex. Bioinformatic analysis showed that among the major pathways altered that were the most dimorphic between WSR and WSP mice were 'acetylation' and 'histone deacetylase complex'. Data shows a complex phenotype-specific regulation during abstinence indicating widespread epigenetic reprogramming in the low response WSR but not the high response WSP mice exposed to the same ethanol concentrations. We will identify phenotype-specific regulatory mechanisms in the low response animal model in three specific aims by integrating data from high-throughput targeting technologies including expression profiling, DNaseI-seq and ChIP-seq, with confirmation of involvement of pathways to modulate relapse using pharmacological intervention in our established dependence-induced relapse drinking model. We hypothesize that targetable epigenetic mechanisms maintain expression differences during abstinence and that these differences increase the risk of relapse in the low response to alcohol endophenotype. These studies have high impact because of the morbidity/mortality associated with alcohol abuse, the high incidence of alcohol use disorders in the general population, and the tremendous impact these maladies have on human health. In addition, neuroadaptive changes and altered expression patterns may also play a role in persistent neurotoxicity and brain damage during abstinence with detrimental consequences for learning and memory functions, to play a role in the down-ward cycle of addiction and the self-sustaining nature of alcoholism. Thus, successful completion of these aims will aid in our understanding of the mechanism(s) underlying the risk for relapse and advance our ability to provide therapy for alcohol abuse targeted to the low response endophenotype, through identification of novel pharmacotherapies or to enhance translational applications for currently available therapeutics with previously unrecognized utility.

Public Health Relevance

Alcohol abuse disorder and addiction are major public health problems in the United States and represent one of the leading preventable causes of death. In this project, we identify epigenetic mechanisms underlying long- term expression differences that persist in the abstinent alcoholic, and examine pharmacological interventions with behavioral validation in a mouse model of the low response to alcohol endophenotype. Successful completion of these studies should help identify therapeutic targets to reverse or reduce risk of relapse drinking and help to maintain sobriety.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Reilly, Matthew
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Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
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Goeke, C M; Roberts, M L; Hashimoto, J G et al. (2018) Neonatal Ethanol and Choline Treatments Alter the Morphology of Developing Rat Hippocampal Pyramidal Neurons in Opposite Directions. Neuroscience 374:13-24
Gavin, David P; Hashimoto, Joel G; Lazar, Nathan H et al. (2018) Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure. Front Genet 9:346
Finn, Deborah A; Hashimoto, Joel G; Cozzoli, Debra K et al. (2018) Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice. Front Genet 9:325
Wilhelm, Clare J; Hashimoto, Joel G; Roberts, Melissa L et al. (2018) Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain. Neuropharmacology 138:193-209
Akinyeke, Tunde; Weber, Sydney J; Davenport, April T et al. (2017) Effects of alcohol on c-Myc protein in the brain. Behav Brain Res 320:356-364
Hashimoto, Joel G; Gavin, David P; Wiren, Kristine M et al. (2017) Prefrontal cortex expression of chromatin modifier genes in male WSP and WSR mice changes across ethanol dependence, withdrawal, and abstinence. Alcohol 60:83-94
Wilhelm, Clare J; Hashimoto, Joel G; Roberts, Melissa L et al. (2016) Astrocyte Dysfunction Induced by Alcohol in Females but Not Males. Brain Pathol 26:433-51
Gavin, David P; Kusumo, Handojo; Sharma, Rajiv P et al. (2016) Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression. Neuropharmacology 110:287-296
Hashimoto, Joel G; Wiren, Kristine M; Wilhelm, Clare J (2016) A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy. Neurotoxicol Teratol 56:35-40
Guizzetti, Marina; Davies, Daryl L; Egli, Mark et al. (2016) Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies. Alcohol Clin Exp Res 40:1182-91

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