Abstract
Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.
Highlights
Alcohol use disorders (AUDs) pose a significant socioeconomic and public health problem worldwide
To test the hypothesis that the High Drinking in the Dark (HDID) selected lines would exhibit higher binge-like drinking than their progenitor line and that ethanol intake would show diurnal variation with increased intake occurring in the dark, we performed Drinking in the Dark (DID) and drinking in the light (DIL) behavioral assays
We report the findings of testing replicate lines of HDID mice, compared to their heterogenous founders, across the following important AUD-related measures: diurnal and temporal limited-access ethanol intake, sensitivity to the sedative effects of ethanol, cue-induced ethanol seeking and the motivation to drink ethanol
Summary
Alcohol use disorders (AUDs) pose a significant socioeconomic and public health problem worldwide. The primary aim of these studies is to finely characterize and compare two replicate lines of mice that were selectively bred to drink to intoxication during a limited period of ethanol access (High Drinking in the Dark-1 and -2; HDID-1 and -2) and compare them to their genetically heterogenous founders, the Heterogeneous Stock/Northport (Hs/Npt) [7,8,9]. Traits on which both HDID lines differ from the non-selected Hs/Npt line can be presumed to reflect the influence of some of the same genes or gene networks underlying risk for DID. HDID-1 and HDID-2 mice are less sensitive to the aversive effects of ethanol than Hs/Npt mice; no line differences were observed in sensitivity to the rewarding effects of ethanol [14]
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