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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    • "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.
    Alcohol 10/2014; DOI:10.1016/j.alcohol.2014.06.009 · 2.01 Impact Factor
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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.
    Drug and alcohol dependence 03/2014; 136(1). DOI:10.1016/j.drugalcdep.2013.12.023 · 3.42 Impact Factor
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    • "HDID mice differ from their HS controls in some, but not all measures of acute ethanol sensitivity and tolerance. While all the tolerance assessments were made well after absorption and distribution of the ethanol injections were complete (Crabbe et al., 2012a), the sensitivity measures targeted both ascending and descending limbs of the BEC curve (Crabbe et al., 2012b). The objective of the current study was to characterize more completely sensitivity and AFT to the ataxic and hypnotic effects of ethanol in HDID mice of the first replicate of selection (HDID "
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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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