A Line of Mice Selected for High Blood Ethanol Concentrations Shows Drinking in the Dark to Intoxication

Portland Alcohol Research Center, Portland, Oregon, USA.
Biological psychiatry (Impact Factor: 10.26). 04/2009; 65(8):662-70. DOI: 10.1016/j.biopsych.2008.11.002
Source: PubMed


Many animal models of alcoholism have targeted aspects of excessive alcohol intake (abuse) and dependence. In the rodent, models aimed at increasing alcohol self-administration have used genetic or environmental manipulations, or their combination. Strictly genetic manipulations (e.g., comparison of inbred strains or targeted mutants, selective breeding) have not yielded rat or mouse genotypes that will regularly and voluntarily drink alcohol to the point of intoxication. Although some behavioral manipulations (e.g., scheduling or limiting access to alcohol, adding a sweetener) will induce mice or rats to drink enough alcohol to become intoxicated, these typically require significant food or water restriction or a long time to develop. We report progress toward the development of a new genetic animal model for high levels of alcohol drinking.
High Drinking in the Dark (HDID-1) mice have been selectively bred for high blood ethanol concentrations (BEC, ideally exceeding 100 mg%) resulting from the ingestion of a 20% alcohol solution.
After 11 generations of selection, more than 56% of the population now exceeds this BEC after a 4-hour drinking session in which a single bottle containing 20% ethanol is available. The dose of ethanol consumed also produced quantifiable signs of intoxication.
These mice will be useful for mechanistic studies of the biological and genetic contributions to excessive drinking.

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Available from: Pamela Metten, Oct 10, 2015
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    • "The DID phenotype is genetically influenced, since studies with inbred mouse strains have indicated similar DID alcohol consumption within strains and different levels of DID alcohol consumption across strains (Rhodes et al. 2007). Furthermore, successful selective breeding for high blood ethanol levels achieved during DID has been accomplished, leading to replicate selected HDID1 and HDID2 mouse lines (Crabbe et al. 2009). In these animals, the blood ethanol concentration correlates with the amount of alcohol consumed in the DID protocol. "
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    ABSTRACT: The ILSXISS (LXS) recombinant inbred (RI) panel of mice is a valuable resource for genetic mapping studies of complex traits, due to its genetic diversity and large number of strains. Male and female mice from this panel were used to investigate genetic influences on alcohol consumption in the “drinking in the dark” (DID) model. Male mice (38 strains) and female mice (36 strains) were given access to 20 % ethanol during the early phase of their circadian dark cycle for four consecutive days. The first principal component of alcohol consumption measures on days 2, 3, and 4 was used as a phenotype (DID phenotype) to calculate QTLs, using a SNP marker set for the LXS RI panel. Five QTLs were identified, three of which included a significant genotype by sex interaction, i.e., a significant genotype effect in males and not females. To investigate candidate genes associated with the DID phenotype, data from brain microarray analysis (Affymetrix Mouse Exon 1.0 ST Arrays) of male LXS RI strains were combined with RNA-Seq data (mouse brain transcriptome reconstruction) from the parental ILS and ISS strains in order to identify expressed mouse brain transcripts. Candidate genes were determined based on common eQTL and DID phenotype QTL regions and correlation of transcript expression levels with the DID phenotype. The resulting candidate genes (in particular, Arntl/Bmal1) focused attention on the influence of circadian regulation on the variation in the DID phenotype in this population of mice.
    Mammalian Genome 01/2015; 26(1-2). DOI:10.1007/s00335-014-9553-8 · 3.07 Impact Factor
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    • "different circa - dian phenotypes . In high and low alcohol - preferring mice ( HAP - 1 and LAP - 1 , respectively ) , HAP - 1 mice have shorter circadian periods in constant darkness ( DD ) than LAP - 1 mice ( Hofstetter , Grahame , & Mayeda , 2003 ) . Other high drinking mouse lines , such as the High Drinking in the Dark ( HDID - 1 and Ϫ2 ) , ( Crabbe et al . , 2009 ; Crabbe , Spence , Brown , & Metten , 2011 ; Rhodes , Best , Belknap , Finn , & Crabbe , 2005 ) , display shorter free - running periods and less coherent activity rhythms in LL relative to the genetically heterogeneous progenitor line ( Hs / Npt ) controls ( Mc - This document is copyrighted by the American Psychological Association o"
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    ABSTRACT: Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Behavioral Neuroscience 04/2014; 128(3). DOI:10.1037/a0036268 · 2.73 Impact Factor
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    • "The observation that the M-AFT and AFT capacity of HDID-1 was similar or even lower than HS/Npt mice may also not be all that surprising given their selection phenotype. The selection phenotype for HDID mice consists of 2 presentations of alcohol: one 2-hour DID access period on day 1 and a 4-hour access period on day 2 (Crabbe et al., 2009). Mice were selected this way because EtOH DID intake on day 2 strongly correlated with intake on subsequent days in studies with C57BL/6J mice, the inbred mouse strain with which the DID paradigm was developed (Rhodes et al., 2005). "
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    ABSTRACT: Initial sensitivity to ethanol (EtOH) and the capacity to develop acute functional tolerance (AFT) to its adverse effects may influence the amount of alcohol consumed and may also predict future alcohol use patterns. The current study assessed sensitivity and AFT to the ataxic and hypnotic effects of EtOH in the first replicate of mice (HDID-1) selectively bred for high blood EtOH concentrations (BECs) following limited access to EtOH in the Drinking in the Dark (DID) paradigm. Naïve male and female HDID-1 and HS/Npt mice from the progenitor stock were evaluated in 3 separate experiments. In Experiments 1 and 2, EtOH-induced ataxia was assessed using the static dowel task. In Experiment 3, EtOH-induced hypnosis was assessed by using modified restraint tubes to measure the loss of righting reflex (LORR). HDID-1 mice exhibited reduced initial sensitivity to both EtOH-induced ataxia (p < 0.001) and hypnosis (p < 0.05) relative to HS/Npt mice. AFT was calculated by subtracting the BEC at loss of function from the BEC at recovery (Experiments 1 and 3) or by subtracting BEC at an initial recovery from the BEC at a second recovery following an additional alcohol dose (Experiment 2). The dowel test yielded no line differences in AFT, but HS/Npt mice developed slightly greater AFT to EtOH-induced LORR than HDID-1 (p < 0.05). These results suggest that HDID-1 mice exhibit aspects of blunted ataxic and hypnotic sensitivity to EtOH which may influence their high EtOH intake via DID, but do not display widely different development of AFT. These findings differ from previous findings with the high alcohol-preferring (HAP) selected mouse lines, suggesting that genetic predisposition for binge, versus other forms of excessive alcohol consumption, is associated with unique responses to EtOH-induced motor incoordination.
    Alcoholism Clinical and Experimental Research 02/2014; 38(5). DOI:10.1111/acer.12385 · 3.21 Impact Factor
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