Selective breeding for high low alcohol preference in mice
ABSTRACT High and low alcohol preference (HAP and LAP, respectively) mice were created by 10 generations of bidirectional selection for differences in two-bottle choice alcohol consumption. The progenitors used for selection were HS/lbg mice, which are a genetically defined, outbred stock. During selection, mice had 24-h, daily access to 10% alcohol (v/v) and water ad libitum for 30 days and were selected based on the alcohol (g/kg) consumed per day over the entire period. Food was available ad libitum. At S10, line means for alcohol consumption differed greatly, with consumption of over 12 g/kg per day in the HAP mice and less than 2 g/kg per day in the LAP mice. Realized heritability for bidirectional selection was approximately 0.2. Female mice consumed more alcohol than male mice. There were no differences between lines in alcohol elimination rate, nor were there line differences in intake of salt or quinine solutions. However, consumption of saccharin solutions was greater in HAP mice than LAP mice, consistent with previous findings of a genetic correlation between sweet preference and alcohol drinking. Because the mouse genome is relatively well characterized, these selected lines should prove a useful tool for assessment of the genetic basis of, and phenotypes that correlate with, alcohol drinking.
- SourceAvailable from: Brandon M Fritz
[Show abstract] [Hide abstract]
- "With repeated cycles of continuous - access 2 - bottle choice drinking , HAP mice typically increase their ethanol intake and preference over days ( Grahame et al . , 1999 ; Matson & Grahame , 2011 ; Oberlin et al . , 2011 ) , and this was generally the case in the current study . Given our previous findings ( Fritz et al . , 2013 ) , we hypothesized that a prior history of alcohol consumption may enhance the already substantial rapid AFT capacity of HAP2 mice . It was found that an ethanol consumption hi"
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 · 2.04 Impact Factor
[Show abstract] [Hide abstract]
- "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). The previous observation of enhanced M-AFT capacity in EtOH-na€ ıve HAP2 and HAP3 mice (Fritz et al., 2013) may be the result of a more protracted selection process as well as more extreme alcohol exposure wherein mice are phenotyped for alcohol preference in a continuous access paradigm over a 30-day period (Grahame et al., 1999). Therefore, the selection protocol for HDID may not have captured genes related to M-AFT or AFT due to a shorter duration of exposure or lesser total dose of alcohol during selection. "
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
[Show abstract] [Hide abstract]
- "Because of the difficulty in directly examining genetic effects in humans, several lines of mice have been developed to help understand the genetic components of alcohol consumption . Such lines include the high-and low-alcohol preferring mice (HAP/LAP; Grahame et al., 1999) and the high-and low-drinking short-term-selected mice (STDRHI/ STDRLO; Phillips et al., 2005). In addition to consumption of alcohol, a number of mice have been selected on other alcohol-related traits, such as sensitivity to alcohol-induced stimulation (FAST/SLOW mice; Crabbe et al., 1987), sensitivity to alcohol-induced loss of righting reflex (short/long sleep mice [SS/LS]; Fuller, 1980), and severity of alcohol withdrawal (after chronic alcohol: Withdrawal Seizure Resistant/Prone mice [WSR/WSP], Kosobud and Crabbe, 1986; after acute alcohol: high-and low-alcohol withdrawal mice [first replicate: HAW-1/LAW-1], Metten et al., 1998a). "
ABSTRACT: BACKGROUND: Mice selectively bred for high or low withdrawal to acute alcohol differ on a number of traits, including consumption of alcohol, conditioned place preference for alcohol, and sensitivity to alcohol-induced locomotor activity. One trait that has not been examined in these mice is behavioral inhibition. METHODS: High and low alcohol withdrawal mice (second replicate: high and low acute alcohol withdrawal [HAW-2/LAW-2]) were trained and tested in a Go/No-go task. Mice were administered 0.0, 0.5, 1.0, and 1.5 g/kg ethanol (EtOH) on 3 occasions according to an incomplete Latin Square. A separate cohort of C57BL/6J (B6) and DBA/2J (D2) mice (the progenitor strains for HAW-2/LAW-2 mice) underwent the same protocol, using the same EtOH doses. RESULTS: HAW-2 and LAW-2 mice did not differ in behavioral inhibition at baseline, although LAW-2 mice did have higher overall levels of responding in the task. EtOH did not alter behavioral inhibition in these mice. However, it did decrease responses to the Go cue, and this effect was greater in HAW-2 mice than in LAW-2 mice. D2 mice had lower behavioral inhibition than B6 mice at baseline, and EtOH slightly decreased behavioral inhibition in both strains. CONCLUSIONS: The findings with D2 and B6 mice generally fit with the existing literature. However, the lack of a difference in behavioral inhibition between HAW-2 and LAW-2 mice was unexpected, as well as the absence of any effect of these doses of EtOH on behavioral inhibition in these mice. Nonetheless, the findings do suggest that selectively breeding for high or low withdrawal to acute alcohol can lead to differences in operant behavior in the Go/No-go task.Alcoholism Clinical and Experimental Research 04/2013; 37(9). DOI:10.1111/acer.12134 · 3.31 Impact Factor