Derivation and Characterization of Replicate High- and Low-Alcohol Preferring Lines of Mice and a High-Drinking Crossed HAP Line
ABSTRACT Selectively breeding lines of mice and rats to differ in alcohol intake has proven useful for defining which traits correlate with high alcohol drinking behavior, as well as for creating animal models of alcoholism. This study reports the derivation of two novel sets of selected lines, High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) replicate 2 and 3 lines. Mice were mass-selected using the same procedure as in the replicate 1 lines: using HS/Ibg as a progenitor, mice were selected for differences in 2-bottle choice intake of 10% alcohol during a 4-week testing period. In addition, another high-drinking line, the crossed HAP (cHAP) line was selectively bred from a progenitors that were a cross of replicate 1 (S27) × replicate 2 (S21) HAP lines. All lines were characterized for saccharin intake. Overall, the response to selection of the HAP and LAP replicate 2 and 3 lines was quite similar. As anticipated, following selection, the cHAP line drank more than either parent HAP line (consuming 26.0 g/kg per day of alcohol by S11), suggesting that this method of crossing replicate lines and selecting from that cross captures more alleles than any single selected line, as well as producing a line with exceptionally high voluntary alcohol intake. As expected, saccharin consumption was highly associated with alcohol consumption; data from 7 lines (HAP 1, 2, and 3, LAP 1, 2, and 3, and cHAP) indicated a genetic correlation between 10% alcohol and 0.32% saccharin intake of 0.91. Overall, these findings show the practicality of developing replicate lines divergent in alcohol preference, and validate a novel procedure for generating very high-drinking mouse populations.
- SourceAvailable from: Brandon M Fritz
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- "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 history produced func tional tolerance to ethanol ' s"
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
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- "Subjects were alcohol-naïve adult male and female HAP2 and LAP2 mice. These mouse lines were selectively bred from a progenitor population of outbred HS/Ibg mice (Institute of Behavioral Genetics, Boulder, CO, USA) at the Indiana Alcohol Research Center in Indianapolis, IN (Oberlin et al. 2011). Subjects were derived from 69 different HAP2 families and 43 different LAP2 families from multiple generations of selection. "
ABSTRACT: Blunted cortisol responses to stress or trauma have been linked with genetic (familial) risk for both alcoholism and post-traumatic stress disorder (PTSD). Mouse lines selectively bred for high (HAP) or low (LAP) alcohol preference may be a relevant model of genetic risk for co-morbid alcoholism and PTSD in humans. HAP mice show greater fear-potentiated startle (FPS), a model used to study PTSD, than LAP mice. The relation between corticosterone (CORT) and FPS behavior was explored in four experiments. Naïve male and female HAP2 and LAP2 mice received fear-conditioning or control treatments, and CORT levels were measured before and immediately after fear-conditioning or FPS testing. In two other experiments, HAP2 mice received CORT (1.0, 5.0 or 10.0 mg/kg) or a glucocorticoid receptor antagonist (mifepristone; 25.0 and 50.0 mg/kg) 30 minutes before fear conditioning. HAP2 mice exposed to fear conditioning and to control foot shock exposures showed lower CORT after the fear-conditioning and FPS testing sessions than LAP2 mice. A trend toward higher FPS was seen in HAP2 mice pretreated with 10.0 mg/kg CORT, and CORT levels were the lowest in this group, suggesting negative feedback inhibition of CORT release. Mifepristone did not alter FPS. Overall, these results are consistent with data in humans and rodents indicating that lower cortisol/CORT levels after stress are associated with PTSD/PTSD-like behavior. These findings in HAP2 and LAP2 mice suggest that a blunted CORT response to stress may be a biological marker for greater susceptibility to develop PTSD in individuals with increased genetic risk for alcoholism.Addiction Biology 01/2013; 19(4). DOI:10.1111/adb.12034 · 5.93 Impact Factor
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- "Naïve adult (postnatal day 60–95) male and female mice from the second and third replicate lines selected for high (HAP2 and HAP3) and low (LAP2 and LAP3) alcohol preference vs. water in twobottle tests were bred on site at the IUPUI School of Science, Indianapolis, IN (for an in-depth description of the selection process and characterization of these lines, see Oberlin et al. 2011). Three replicates of the HAP/LAP lines now exist, and there are extreme differences in alcohol intake and preference with the replicate HAP lines consuming high intoxicating amounts of alcohol and replicate LAP lines demonstrating relative avoidance (Oberlin et al. 2011). Selected lines are particularly useful animal models to study genetic risk for alcohol abuse because they allow the researcher to theoretically fix only alleles that are specific to the phenotype of interest (in this case, alcohol preference) through selective mating. "
ABSTRACT: Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of this study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2 and HAP3) and low (LAP2 and LAP3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task, which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75 g/kg; Experiment 1) or two (1.75 and 2.0 g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance [when blood ethanol concentrations (BECs) were rising] and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice when compared with LAP mice, which occurred within ∼30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ∼30-60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.Genes Brain and Behavior 07/2012; 12(1). DOI:10.1111/j.1601-183X.2012.00830.x · 3.51 Impact Factor