Ethanol Tolerance and Withdrawal Severity in High Drinking in the Dark Selectively Bred Mice

Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health, Portland, OR 97239, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 02/2012; 36(7):1152-61. DOI: 10.1111/j.1530-0277.2011.01715.x
Source: PubMed


Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark-1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are 2 of the 7 diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking.
To determine other traits genetically correlated with high DID, we compared naïve animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits.
Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their third daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2, and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment.
These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to EtOH responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.

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    • "The same adaptations that produce functional tolerance have been linked to physiological dependence and the accompanying symptoms of ethanol withdrawal (Ghezzi & Atkinson, 2011;Koob & Le Moal, 2006;Martin, 1968). However, the correlation between the capacity to acquire tolerance and increased drinking behavior is complex, and may depend both on the way tolerance was induced and the way it was measured (Crabbe et al., 2012;Fritz, Grahame, & Boehm, 2013;Matson, Kasten, Boehm, & Grahame, 2014). Nevertheless, it is probable that the later M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT adaptations, which produce the addicted state, bear some resemblance to or are built upon the early adaptations that underlie tolerance. "
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    ABSTRACT: In Drosophila, the slo gene encodes BK-type Ca2+-activated K+ channels and is involved in producing rapid functional tolerance to sedation with ethanol. Drosophila are ideal for the study of functional ethanol tolerance because the adult does not acquire metabolic ethanol tolerance (Scholz, Ramond, Singh, & Heberlein, 2000). It has been shown that mutations in slo block the capacity to acquire tolerance, that sedation with ethanol vapor induces slo gene expression in the nervous system, and that transgenic induction of slo can phenocopy tolerance (Cowmeadow, Krishnan, & Atkinson, 2005; Cowmeadow et al., 2006). Here we use ethanol-induced histone acetylation to map a DNA regulatory element in the slo transcriptional control region and functionally test the element for a role in producing ethanol tolerance. Histone acetylation is commonly associated with activating transcription factors. We used the chromatin-immunoprecipitation assay to map histone acetylation changes following ethanol sedation to identify an ethanol-responsive DNA element. Ethanol sedation induced an increase in histone acetylation over a 60 n DNA element called 6b, which is situated between the two ethanol-responsive neural promoters of the slo gene. Removal of the 6b element from the endogenous slo gene affected the production of functional ethanol tolerance as assayed in an ethanol-vapor recovery from sedation assay. Removal of element 6b extended the period of functional ethanol tolerance from ∼10 days to more than 21 days after a single ethanol-vapor sedation. This study demonstrates that mapping the position of ethanol-induced histone acetylation is an effective way to identify DNA regulatory elements that help to mediate the response of a gene to ethanol. Using this approach, we identified a DNA element, which is conserved among Drosophila species, and which is important for producing a behaviorally relevant ethanol response.
    Full-text · Article · Jan 2016
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    • "n important factor in the escalating ethanol consumption of HAP2 mice over the course of continuous - access drinking . Numerous studies with selectively bred rodent lines have demonstrated that a genetic predisposition for various forms of excessive alcohol consumption is associated with unique responses to alcohol intoxication in naïve animals ( Crabbe , Kruse , et al . , 2012 ; Fritz et al . , 2013 , 2014 ; Grahame et al . , 2000 ; Waller et al . , 1983 ) ."
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    ABSTRACT: We have previously shown that ethanol-naïve high-alcohol preferring (HAP) mice, genetically predis-posed to consume large quantities of alcohol, exhibited heightened sensitivity and more rapid acute functional tolerance (AFT) to alcohol-induced ataxia compared to low-alcohol preferring mice. The goal of the present study was to evaluate the effect of prior alcohol self-administration on these responses in HAP mice. Naïve male and female adult HAP mice from the second replicate of selection (HAP2) un-derwent 18 days of 24-h, 2-bottle choice drinking for 10% ethanol vs. water, or water only. After 18 days of fluid access, mice were tested for ataxic sensitivity and rapid AFT following a 1.75 g/kg injection of ethanol on a static dowel apparatus in Experiment 1. In Experiment 2, a separate group of mice was tested for more protracted AFT development using a dual-injection approach where a second, larger (2.0 g/kg) injection of ethanol was given following the initial recovery of performance on the task. HAP2 mice that had prior access to alcohol exhibited a blunted ataxic response to the acute alcohol challenge, but this pre-exposure did not alter rapid within-session AFT capacity in Experiment 1 or more protracted AFT capacity in Experiment 2. These findings suggest that the typically observed increase in alcohol consumption in these mice may be influenced by ataxic functional tolerance development, but is not mediated by a greater capacity for ethanol exposure to positively influence within-session ataxic tolerance.
    Full-text · Article · Oct 2014 · Alcohol
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    • "Thus, it is unsurprising that these lines, while both showing high BECs in DID, differ on other behaviors, including the present impulsivity task. For example, these lines have been shown to differ in their loss of righting reflex and footslips following acute ethanol, but have similar responses on a balance beam test, in acute withdrawal severity, and in hypothermic responses to ethanol (Crabbe et al., 2012a, 2012b). Thus, while this selection process successfully captured the target behavior, a subset of other alcohol-related behaviors, including Go/No-Go performance, was not captured identically across these two lines. "
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    ABSTRACT: Background Alcohol consumption and behavioral inhibition share some common underlying genetic mechanisms. The current study examined whether lines of mice selected for high blood ethanol concentrations, attained by heavy drinking in the dark period (DID) of the light-dark cycle that models binge drinking, also exhibit higher levels of drug-naïve inhibition. It also examined whether the administration of ethanol would result in higher levels of disinhibition in these selected lines compared to the founder stock (HS). Methods. A Go/No-Go task was used to assess baseline inhibition and the effects of acute ethanol on disinhibition (response to a No-Go cue) in the HS line and in mice selected for high levels of DID (HDID-1 and HDID-2). Results Lines did not differ in inhibition at baseline and all lines showed increased disinhibition following moderate doses of ethanol. Ethanol decreased responding to Go cues for HDID-2 and HS lines at high doses but not HDID-1 mice. Conclusions. These data corroborate previous work showing ethanol-induced increases in behavioral disinhibition. The selection paradigm did not result in differential sensitivity to the disinhibiting effects of ethanol, but did result in differential sensitivity to the suppressant effects of ethanol on operant behavior between the two HDID lines.
    Full-text · Article · Mar 2014 · Drug and alcohol dependence
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