Genetic analysis of the psychomotor stimulant effect of ethanol.

Genetic influences on the psychomotor stimulant effect of ethanol may be a key feature of abuse liability. While earlier work has shown the activational effects of ethanol to be under the influence of a relatively uncomplicated additive genetic system, preliminary data from our laboratory suggested the possibility of nonadditive genetic variance. In the present study, a full Mendelian cross was conducted to further characterize gene action and search for quantitative trait loci (QTL) influencing the psychomotor stimulant properties of ethanol. We tested 3062 mice of the six Mendelian cross genotypes (P1, P2, F1, F2, BC1 and BC2) derived from a cross between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice. On day 1, mice were injected with saline, put in a holding cage for 5 min, then placed in an activity monitor for 5 min. On day 2, mice were injected with 1.5 g/kg ethanol, and activity again monitored for 5 min. Analysis showed the expected activation in the C3H strain and little activation in the B6 strain, with no effect of sex. Biometrical genetic analysis showed a best-fit model that included the mean (m), additive effect (a), and an epistatic parameter (i = homozygote by homozygote interaction). Analysis showed good evidence for QTL on chromosomes 1 (logarithm of odds (LOD) 3.4-7.5, 88-100 cM), 6 (LOD 9.1-10.4, 46-50 cM) and 15 (LOD 7.3-8.8, 28-32 cM). While the regions on chromosomes 1 and 6 have previously been implicated in several different ethanol-related phenotypes, this is the first report of a QTL influencing the psychomotor stimulant properties of ethanol on chromosome 15. Other studies have identified QTL in this region of chromosome 15 mediating locomotor activation caused by other psychostimulants, including cocaine, amphetamine and phencyclidine.

Alcohol place preference conditioning in high- and low-alcohol preferring selected lines of mice.

High- and low-alcohol preferring (HAP and LAP) selected lines of mice diverge greatly in free-choice alcohol consumption. This study investigated whether the lines differ in a measure of alcohol reward not dependent on drinking, specifically place conditioning. Mice were subjected to a differential conditioning procedure in which four alcohol-paired CS+ trials on one floor cue (0, 1.5, 3, or 4 g/kg; ns=20-24) alternated with four saline-paired CS- trials on a different floor cue. Testing was on a split floor, half CS+ and half CS-. HAP and LAP mice showed no preference at 0 g/kg, and equivalent, moderate preference at 1.5 and 3 g/kg alcohol. At 4 g/kg, LAP, but not HAP mice showed an increase in preference. The present findings imply greater efficacy of alcohol preference conditioning in LAP mice, but do not speak for line differences in sensitivity. Results do not support the hypothesis that selection for high drinking yields greater efficacy of alcohol as a reinforcer when reward is measured using a technique that does not rely on drinking. Low drinking in LAP mice may emerge from innate taste avoidance of alcohol as a result of selective breeding for low preference, which prevents them from encountering alcohol's rewarding, pharmacological effects.

Ethanol locomotor sensitization, but not tolerance correlates with selection for alcohol preference in high- and low-alcohol preferring mice.

RATIONALE: Some theories have advanced a role for both locomotor sensitization and tolerance in the reinforcing properties of drugs. The present studies used selected lines of mice to assess genetic correlations among ethanol drinking, ethanol locomotor sensitization, and tolerance to the depressant effects of ethanol. OBJECTIVES: Ethanol-naive high- and low-alcohol preferring (HAP and LAP) selected lines of mice were tested for locomotor sensitization to ethanol and acquisition of acute functional tolerance to ethanol using the static dowel test. METHODS: For the locomotor sensitization study, mice received four i.p. injections of one of five doses of ethanol (0-3.5 g/kg) at 48-h intervals. On the sensitization test day, 48 h after the last drug administration day, all mice received a 2.0-g/kg ethanol injection. Other mice from the same lines were subjected to a two-injection (3.75 g/kg total), acute functional tolerance procedure assessing disruption of balance on a static dowel. RESULTS: Lines differed neither in the acute locomotor activating nor depressant effects of ethanol. Additionally, neither line's response to the depressant effect of 3.5 g/kg ethanol changed with repeated injection. However, locomotor sensitization was seen in HAP but not LAP mice that had received 2.75 g/kg or 3.5 g/kg ethanol during repeated administration. Both HAP and LAP mice acquired equivalent acute functional tolerance, as measured by an increase in blood ethanol concentration between the first and second recovery measures. CONCLUSIONS: Overall, these findings imply that high ethanol consumption in mice appears to be genetically related to ethanol locomotor sensitization. Additionally, ethanol locomotor sensitization does not appear to be related to tolerance to the depressant effects of ethanol. These findings support a role for sensitization in high alcohol-seeking behavior in mice.