The Genetic Complexity of Alcohol Drinking in Rodents

Crabbe, John C.

doi:10.1016/b978-0-12-405941-2.00018-3

Cited by 7 publications

(9 citation statements)

References 168 publications

(136 reference statements)

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“…It also showed specificity in that this dose did not reduce either water or saccharin intake during subsequent tests (Figure 3). This suggests that the reduced ethanol intake was related to ethanol’s pharmacological and/or behavioral effects rather than through more general mechanisms such as reduced caloric drive, motivation for fluids, taste alteration, or general malaise 19 . However, the reductions in ethanol intake did not result in significantly lower BALs at the end of the drinking sessions.…”

Section: Discussionmentioning

confidence: 99%

“…C57BL/6J mice have long been known to drink more alcohol than other inbred strains 17 , but they represent a single genotype: that is, all same-sex animals have 2 copies of the same gene-specific allele for every gene, making them in some sense like a set of clones. This inbred state may limit the generalizability of findings to other mouse inbred strains and genetically segregating genotypes 18;19 . Each human, on the other hand, is genetically unique (with the exception of identical twins).…”

Section: Introductionmentioning

confidence: 99%

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High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

Crabbe

Ozburn

Metten

et al. 2017

Pharmacology Biochemistry and Behavior

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Background There is a serious public health need for better understanding of alcohol use disorder disease mechanisms and for improved treatments. At this writing, only three drugs are approved by the Food and Drug Administration as medications to treat alcohol use disorders – disulfiram, naltrexone, and acamprosate. Binge drinking is a form of abusive alcohol drinking defined by the NIAAA as a drinking to blood alcohol levels (BALs) > 0.08% during a period of approximately 2 hr. To model genetic risk for binge-like drinking, we have used selective breeding to create a unique animal model, High Drinking in the Dark (HDID) mice. Behavioral characterization of HDID mice has revealed that HDID mice exhibit behavioral impairment after drinking, withdrawal after a single binge-drinking session, and escalate their intake in response to induction of successive cycles of dependence. Notably, HDID mice do not exhibit altered tastant preference or alcohol clearance rates. We therefore asked whether drugs of known clinical relevance could modulate binge-like ethanol drinking in HDID mice, reasoning that this characterization of HDID responses should inform future use of this genetic animal model for screening and development of novel potential therapeutics. Methods We tested the efficacy of acamprosate and naltrexone to reduce binge-like drinking in HDID mice. Additionally, we tested the GABAB receptor agonist, baclofen, based on recent pre-clinical and clinical studies demonstrating that it reduces alcohol drinking. We elected not to include disulfiram due to its more limited clinical usage. Mice were tested after acute doses of drugs in the limited-access Drinking in the Dark (DID) paradigm. Results HDID mice were sensitive to the effects of acamprosate and baclofen, but not naltrexone. Both drugs reduced binge-like drinking. However, naltrexone failed to reduce drinking in HDID mice. Thus, HDID mice may represent a useful model for screening novel compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

Crabbe

Ozburn

Metten

et al. 2017

Pharmacology Biochemistry and Behavior

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“…Although the heritability of the HDID phenotype is relatively low (~ 0.1), selection has raised the average BEC at the end of the DID trial to > 1.8 mg/ml. This BEC is 5–6 fold greater than the average BEC obtained in the founder heterogeneous stock animals (HS/NPT) ( Barkley-Levenson and Crabbe, 2014; Crabbe et al 2014). One assumes given the duration of selection that any remaining genetic diversity, relevant to the selection phenotype, would only be found only in genes with very small effect sizes.…”

Section: Introductionmentioning

confidence: 58%

Alignment of the transcriptome with individual variation in animals selectively bred for High Drinking-In-the-Dark (HDID)

Hitzemann

Oberbeck

Iancu

et al. 2017

Alcohol

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Among animals at risk for excessive ethanol consumption such as the HDID selected lines, there is considerable individual variation in the amount of ethanol consumed and the associated blood ethanol concentrations (BECs). For the HDID lines, this variation occurs even though the residual genetic variation associated with the DID phenotype has been largely exhausted and thus is most likely associated with epigenetic factors. Here we focus on the question of whether the genes associated with individual variation in HDID-1 mice are different from those associated with selection (risk) ( Iancu et al. 2013). Thirty-three HDID-1 mice were phenotyped for their BECs at the end of a standard DID trial, were sacrificed 3 weeks later and RNA-Seq was used to analyze the striatal transcriptome. The data obtained illustrated that there is considerable overlap of the risk and variation gene sets; both focus on the fine tuning of synaptic plasticity.

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“…The DID phenotype captures some aspects of binge consumption. Data were collected from the two selected lines, (HDID-1 & −2) which routinely reach a blood alcohol level of > 150 mg% (Crabbe, 2014), and the heterogeneous stock (HS/NPT) founders. The HS/NPT founders capture approximately 30% of the genetic variance that is available in Mus musculus (Roberts, Pardo-Manuel de Villena, Wang, McMillan & Threadgill, 2007).…”

Section: Brain Transcription Changes In the Mouse And Macaque Brain Amentioning

confidence: 99%

Cross-species molecular dissection across alcohol behavioral domains

Farris

Riley

Williams

et al. 2018

Alcohol

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This review summarizes the proceedings of a symposium presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference held in Volterra, Italy on May 9-12, 2017. Psychiatric diseases, including alcohol-use disorders (AUDs), are influenced through complex interactions of genes, neurobiological pathways, and environmental influences. A better understanding of the common neurobiological mechanisms underlying an AUD necessitates an integrative approach, involving a systematic assessment of diverse species and phenotype measures. As part of the World Congress on Stress and Alcoholism, this symposium provided a detailed account of current strategies to identify mechanisms underlying the development and progression of AUDs. Dr. Sean Farris discussed the integration and organization of transcriptome and postmortem human brain data to identify brain regional- and cell type-specific differences related to excessive alcohol consumption that are conserved across species. Dr. Brien Riley presented the results of a genome-wide association study of DSM-IV alcohol dependence; although replication of genetic associations with alcohol phenotypes in humans remains challenging, model organism studies show that COL6A3, KLF12, and RYR3 affect behavioral responses to ethanol, and provide substantial evidence for their role in human alcohol-related traits. Dr. Rob Williams expanded upon the systematic characterization of extensive genetic-genomic resources for quantifying and clarifying phenotypes across species that are relevant to precision medicine in human disease. The symposium concluded with Dr. Robert Hitzemann's description of transcriptome studies in a mouse model selectively bred for high alcohol ("binge-like") consumption and a non-human primate model of long-term alcohol consumption. Together, the different components of this session provided an overview of systems-based approaches that are pioneering the experimental prioritization and validation of novel genes and gene networks linked with a range of behavioral phenotypes associated with stress and AUDs.

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The Genetic Complexity of Alcohol Drinking in Rodents

Cited by 7 publications

References 168 publications

High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

Alignment of the transcriptome with individual variation in animals selectively bred for High Drinking-In-the-Dark (HDID)

Cross-species molecular dissection across alcohol behavioral domains

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