Biochemical genetic variants in mice selectively bred for sensitivity or resistance to ethanol‐induced sedation

Abstract

The distribution of biochemical genetic variants was examined among eight inbred strains of mice, which served as contributors to a heterogeneous stock of mice (HS), and in short-sleep (SS) and long-sleep (LS) mice, selectively bred from the HS stock for differential ethanol sensitivity. Fifteen loci for enzymes of alcohol and aldehyde metabolism, as well as 12 other biochemical loci, were investigated. Thirteen of these loci exhibited allelic variation between strains, of which six were separately fixed in the SS and LS mice. Comparisons of genetic similarity coefficients, based upon the distributions of allelic variants for the loci examined, with behavioural sensitivities (sleep-time) to an acute dose of ethanol for the inbred and selected strains of mice, indicated no correlations between these data. This suggests that this collective group of loci are not useful indicators of the genes selectively bred in the SS and LS strains, which are responsible for the differential sensitivities to acute doses of ethanol.

Mapping of Quantitative Trait Loci Underlying Ethanol Metabolism in BXD Recombinant Inbred Mouse Strains

“…It is noteworthy that neither of the known genetic determinants of EtOH metabolism in humans was identified in this murine screen (e.g., Chambers, 1990;Chen et al, 1999a;Hittle and Crabb, 1988;Shen et al, 1997). Although there are polymorphic alleles for both ALDH and ADH in the BXD RI strains (Holmes et al, 1986;Miles et al, 1991;Rout and Holmes, 1996), there was no suggestion that these gene products contributed to strain variation in metabolism in this study. However, the gene for the EtOHinducible cytochrome P4502e1 (Cyp2e1), located on distal chromosome 7, was significantly associated with BECs after both doses.…”

Common Factors Underlying Diverse Responses in Alcohol Use Disorder

“…Pharmacogenomic studies of alcohol response have established that interindividual variation in responses is both pharmacokinetic in origin, as illustrated by ADH1B and ALDH2 variants that cause alcohol‐induced flushing ( 6 ), and pharmacodynamic, as illustrated by lack of difference in alcohol metabolism to explain variation in alcohol‐induced sedation in humans ( 9 ) and mice ( 10 ). Overall, genetic sources of variability in response remain poorly understood, restricting insights into physiologic mechanisms, the extent to which these response phenotypes are independent or co‐determined, and relationships to other heritable phenotypes.…”