US veterans have higher prevalence rates than the general population for Alcohol Use Disorders (AUD) and binge drinking. This project has established several genetic animal models for aspects of AUD. We are employing a mouse model of binge-like drinking to intoxication to study the risks for and consequences of such binge-like drinking on networks of brain genes. Using transcriptional data from a genetic screen of nave High Drinking in the Dark (HDID) mice, we identified as a druggable target the extracellular matrix (ECM). We will investigate drugs that affect the ECM for efficacy to reduce binge-like drinking. We will combine studies of the brain pathways of binge drinking with genome analyses to identify novel drugs that will be tested to see whether they can prevent withdrawal-induced escalated drinking. Specifically, we will determine the transcriptional changes associated with withdrawal-escalated consumption in HDID mice of both sexes. We will use transcriptional data from two brain areas, nucleus accumbens shell (NAS) and the lateral orbital frontal cortex (LOC), both known to be associated with binge consumption, to screen databases to find compounds that can be tested for possible reduction of withdrawal-escalated consumption. After 6 weeks of drinking in the dark (a binge-like procedure, DID), mice will be exposed to 6 repeated cycles of intermittent ethanol vapor inhalation followed by access to drinking, or only to air. After completion of this protocol, drinking will have escalated and brains will be harvested for laser microcapture of NAS and LOC. RNA-Seq will be performed on these tissues to obtain transcriptional data. Network-centric analyses will identify key hub nodes and/or pathways that can be targeted for manipulation by compounds nominated by database searches (e.g., the Library of Integrated Network-Based Cellular Signatures: LINCS). We will then determine whether a nominated compound is effective in reducing post-escalation drinking. We have nearly 40 years experience with vapor inhalation and our detailed methodology for chronic intermittent vapor inhalation and withdrawal have been published. We have also published data showing increased drinking by HDID mice after repeated withdrawal episodes using the chronic intermittent exposure (CIE) vapor inhalation model.
The VA?s leadership in substance abuse, a VA Research Priority Area, and in particular alcohol research is well known. Alcohol-related disorders (AUDs) have consistently been diagnosed in a large proportion of VA hospital patients. Female and male veterans also have much higher prevalence rates than the general population. In a review of more than 456,000 Iraq and Afghanistan Veterans, about 1 in 10 had an AUD. This project focuses on a primary problem of nearly all patients with an AUD diagnosis: relapse to drinking during alcohol withdrawal. We are employing a mouse model of binge-like drinking to intoxication to study the risks for and consequences of such binge-like drinking on networks of brain genes. We combine studies of the brain pathways of binge drinking with genome analyses to identify novel drugs that will be tested to see whether they can prevent relapse drinking.
|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|
|Purohit, Kush; Parekh, Puja K; Kern, Joseph et al. (2018) Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice. Alcohol Clin Exp Res 42:879-888|
|Metten, Pamela; Schlumbohm, Jason P; Huang, Lawrence C et al. (2018) An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice. Alcohol 68:19-35|
|Crabbe, John C; Ozburn, Angela R; Metten, Pamela et al. (2017) High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking. Pharmacol Biochem Behav 160:55-62|
|Jensen, Jeremiah P; Nipper, Michelle A; Helms, Melinda L et al. (2017) Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal. Psychopharmacology (Berl) 234:2793-2811|
|Greenberg, Gian D; Phillips, Tamara J; Crabbe, John C (2016) Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity. Physiol Behav 165:257-66|
|Greenberg, G D; Huang, L C; Spence, S E et al. (2016) Nest building is a novel method for indexing severity of alcohol withdrawal in mice. Behav Brain Res 302:182-90|
|Crabbe, John C; Schlumbohm, Jason P; Hack, Wyatt et al. (2016) Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking. Alcohol 52:25-32|
|Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51|
|Crabbe, John C (2016) Reproducibility of Experiments with Laboratory Animals: What Should We Do Now? Alcohol Clin Exp Res 40:2305-2308|
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