Genetic Dissociation Between Ethanol Sensitivity and Rapid Tolerance in Mouse and Rat Strains Selectively Bred for Differential Ethanol Sensitivity

Abstract

The Inbred Long- and Short-Sleep mice (ILS and ISS) and the Inbred High- and Low-Alcohol-Sensitive rats (IHAS and ILAS) were selectively bred for differential alcohol sensitivity with use of the duration of loss-of-righting-reflex test (LORR), with the IHAS and ILS animals being much more sensitive than the ILAS and ISS animals, respectively. The current study was undertaken to determine whether acute sensitivity in these strains is genetically correlated to a rapid tolerance to alcohol, a form of tolerance that is evident 24 hr after a single alcohol dose. Separate groups of animals were administered a single pretreatment dose of alcohol (0-6 g/kg for the mice; 0-4 g/kg for the rats). Alcohol sensitivity was tested 24 hr later with the LORR test, and blood ethanol concentration was tested at regain of righting (BECRR). Alcohol-induced hypothermia also was determined in the mice. Independently derived replicate rat strains were used for all experiments (IHAS1, ILAS1; IHAS2, ILAS2); no such replicates exist for the ILS and ISS strains. Alcohol pretreatment caused a dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the ILS strain, but LORR increased in the ISS strain with no effect on BECRR. Both strains became hypothermic during the LORR test on day two, but the only significant effect of alcohol pretreatment was in the ISS strain, in which alcohol-induced hypothermia was enhanced. Alcohol pretreatment caused a significant dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the IHAS1 but not in the IHAS2 strain. In contrast, ILAS1 and ILAS2 strains both showed a significant increase in LORR duration and also a significant increase in BECRR. Alcohol pretreatment caused a dose-dependent decrease in LORR duration and an increase in BECRR in the IHAS1 and ILS strain, suggesting the development of functional rapid tolerance. In contrast, LORR duration increased in the ILAS1, ILAS2, and ISS groups, but BECRR either increased (ILAS1, ILAS2) or did not change (ISS). These observations suggest that central nervous system sensitivity was decreased in the ILAS1 and ILAS2 groups (i.e., rapid functional tolerance) or unchanged in the ISS strain, but that some pharmacokinetic property also was altered in these strains. Overall, the results do not support a genetic relation between alcohol sensitivity and the development of rapid tolerance.