Ethanol-induced activation and rapid development of tolerance may have some underlying genes in common

Ethanol exerts biphasic effects on behavior, stimulant at low doses and depressant at higher doses. In the present study we used two mouse genetic models to investigate the relationships among activating and depressant responses to alcohol. The first model was a panel of nine isogenic genotypes. FAST and SLOW mice, selectively bred for high and low ethanol-induced motor activation, respectively, were used as a second model. We used loss of righting reflex to assess initial sensitivity and acute functional tolerance to a hypnotic dose of ethanol (3 g/kg, 20% v/v). Blood ethanol concentration at the onset of loss of righting reflex was used as an estimate of initial sensitivity, while the difference between concentration values at the recovery and loss of righting represented an acute functional tolerance score. Mean initial sensitivity and acute functional tolerance values of the nine strains were correlated with a previously obtained measure of ethanol-induced locomotor activation. Activation correlated significantly with both initial sensitivity (r_g = 0.80; P < 0.05) and acute functionall tolerance (r_g = 0.77; P < 0.05). Thus, inbred genotypes that were activated more by a low dose of ethanol were also more sensitive to and developed more acute tolerance to a high dose. FAST mice had initial sensitivity values similar to those of SLOW mice, but developed more pronounced tolerance, indicating that ethanol-induced activation and acute functional tolerance may be regulated by some common genetic mechanisms. In summary, these results supported a genetic association between ethanol-induced activation and rapid development of tolerance.