The effect of prior alcohol consumption on the ataxic response to alcohol in high-alcohol preferring mice

Abstract

We have previously shown that ethanol-naïve high-alcohol preferring (HAP) mice, genetically predisposed 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) underwent 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.

Keywords: Alcohol; Alcohol consumption; Ataxia; Mouse; Selected lines; Tolerance.

Fig. 1

Ethanol intake and preference of HAP2 mice in the 2-bottle choice paradigm in which mice had a choice between 10% (v/v) ethanol and water in Experiment 1 (n = 12–14). A) Weight-based dose of ethanol consumed, averaged per day. B) Preference index for the volume of 10% ethanol consumed relative to water. Dashed line indicates an ethanol preference of 50%, with values above this line indicating ethanol preference. **p < 0.01; ***p < 0.001 for main effect of sex; ^#p < 0.05 vs. males.

Fig. 2

Static dowel assessment of sensitivity and M-AFT to ataxia induced by a 1.75 g/kg injection of ethanol in Experiment 1 (n = 12–15 per group/sex combination). A) Latency to ‘loss of function’ (LOF) following the ethanol injection. B) BEC values at LOF (intoxication assessment on the ascending limb) and recovery (descending limb). C) Time taken to reach the 1-min recovery criterion following the injection of ethanol. D) M-AFT was calculated as the difference between BEC at recovery and LOF. **p < 0.01; ***p < 0.001 vs. W; ^#p < 0.05 vs. males; ^&&&p < 0.001 vs. zero.

Fig 3

Ethanol intake and preference in HAP2 mice that had access to both 10% ethanol and water in Experiment 2 (n = 13). A) Weight-based dose of ethanol consumed, averaged per day. B) Preference index for the volume of 10% ethanol consumed relative to water. Dashed line indicates an ethanol preference of 50% with values above this line indicating ethanol preference. ***p < 0.001 for main effect of sex.

Fig. 4

Static dowel assessment of AFT to ataxia induced by 1.75 g/kg and 2.0 g/kg injections of ethanol in Experiment 2 (n = 11–13 per group/sex combination). A) Latency to ‘loss of function’ (LOF) following the ethanol injection. B) BEC values at LOF (intoxication assessment on the ascending limb) and recovery (descending limb). C) Time taken to reach the 1-min recovery criterion following the injection of ethanol. D) AFT was calculated as the difference between BEC at recovery 2 and recovery 1. **p < 0.001 vs. W; ^#p < 0.05 vs. males; ^p < 0.05 for E females vs. W females; ^%p = 0.053 for E females vs. W females.