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Crabbe JC, Spence SE, Brown LL, Metten P. Alcohol preference drinking in a mouse line selectively bred for high drinking in the dark. Alcohol 45: 427-440

Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health & Science University and VA Medical Center, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.04). 12/2010; 45(5):427-40. DOI: 10.1016/j.alcohol.2010.12.001
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ABSTRACT We have selectively bred mice that reach very high blood ethanol concentrations (BECs) after drinking from a single bottle of 20% ethanol. High Drinking in the Dark (HDID-1) mice drink nearly 6g/kg ethanol in 4h and reach average BECs of more than 1.0mg/mL. Previous studies suggest that DID and two-bottle preference for 10% ethanol with continuous access are influenced by many of the same genes. We therefore asked whether HDID-1 mice would differ from the HS/Npt control stock on two-bottle preference drinking. We serially offered mice access to 3-40% ethanol in tap water versus tap water. For ethanol concentrations between 3 and 20%, HDID-1 and HS/Npt controls did not differ in two-bottle preference drinking. At the highest concentrations, the HS/Npt mice drank more than the HDID-1 mice. We also tested the same mice for preference for two concentrations each of quinine, sucrose, and saccharin. Curiously, the mice showed preference ratios (volume of tastant/total fluid drunk) of about 50% for all tastants and concentrations. Thus, neither genotype showed either preference or avoidance for any tastant after high ethanol concentrations. Therefore, we compared naive groups of HDID-1 and HS/Npt mice for tastant preference. Results from this test showed that ethanol-naive mice preferred sweet fluids and avoided quinine but the genotypes did not differ. Finally, we tested HDID-1 and HS mice for an extended period for preference for 15% ethanol versus water during a 2-h access period in the dark. After several weeks, HDID-1 mice consumed significantly more than HS. We conclude that drinking in the dark shows some genetic overlap with other tests of preference drinking, but that the degree of genetic commonality depends on the model used.

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    • "This pharmacological evidence reinforces the view that the D 3 R is necessary for ethanol consumption in mice and is consistent with rat data showing that D 3 R antagonism reduces relapse-like drinking and cue-induced ethanol-seeking behavior (Vengeliene et al, 2006). We confirmed the primary role of D 3 R in the control of ethanol-drinking behavior in a binge-like ethanol-drinking paradigm (Crabbe et al, 2011; Rhodes et al, 2005; Rhodes et al, 2007). Here, again, D 3 R À / À mice exposed to DID drank lower quantities of ethanol in comparison with their WT littermates, and D 3 R blockade by SB277011A decreased ethanol intake in WT but not in D 3 R À / À . "
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    ABSTRACT: Mesolimbic dopamine (DA) controls drug and alcohol seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R deficient mice (D3R(-/-)) and their wild type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R(-/-) and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R(-/-) mice. Ethanol intake increased the expression of RACK1 and BDNF in both WT and D3R(-/-); in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.Neuropsychopharmacology accepted article preview online, 3 March 2014; doi:10.1038/npp.2014.51.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2014; 39(8). DOI:10.1038/npp.2014.51 · 7.83 Impact Factor
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    • "Our goal was to compare baseline and post-ethanol levels of inhibitory behavior using a Go/No-Go task in two replicate lines of mice selected from a segregating stock HS/Npt (HS) to achieve high BECs during a drinking in the dark (DID) paradigm (high drinking in the dark [HDID]-1 and 2; Crabbe et al., 2009, 2011b). The DID paradigm, in which high BECs are obtained in a short time period, is commonly used to model binge drinking (Crabbe et al., 2011a). "
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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. DOI:10.1016/j.drugalcdep.2013.12.023 · 3.28 Impact Factor
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    • "By evaluating the alcohol intake of HAP mice using DID procedures and HDID mice in a continuous access 2- bottle choice paradigm, previous studies have explored the genetic overlap of these drinking phenotypes. Employing a slightly modified DID paradigm (daily 4-hour access to 20% v/v EtOH), HAP-1 mice (generation 46) were observed to consume high amounts of alcohol (~7.5 g/kg), whereas LAP- 1 mice exhibited rather low intake (~2.5 g/kg) (Crabbe et al., 2011). It therefore appears that divergent genetic selection for high or low alcohol preference produced analogous drinking behavior in the limited access DID paradigm (although DID drinking behavior has not yet been evaluated in HAP/LAP-2 or HAP/LAP-3, the lines which were tested in Fritz et al. [2013]). "
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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 · 3.31 Impact Factor
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