A major QTL for acute ethanol sensitivity in the alcohol tolerant and non‐tolerant selected rat lines

Abstract

The Alcohol Tolerant and Alcohol Non-Tolerant rats (AT, ANT) were selectively bred for ethanol-induced ataxia as measured on the inclined plane. Here we report on a quantitative trait locus (QTL) study in an F 2 intercross population derived from inbred AT and ANT (IAT, IANT) and a follow-up study of congenics that were bred to examine one of the mapped QTLs. Over 1200 F 2 offspring were tested for inclined plane sensitivity, acute tolerance on the inclined plane, duration of the loss of righting reflex (LORR) and blood ethanol at regain of the righting reflex (BECRR). F 2 rats that were in the upper and lower 20% for inclined plane sensitivity were genotyped with 78 SSLP markers. Significant QTLs for inclined plane sensitivity were mapped on chromosomes 8 and 20; suggestive QTLs were mapped on chromosomes 1, 2 and 3. Highly significant QTLs for LORR duration (LOD = 12.4) and BECRR (LOD = 5.7) were mapped to the same locus on chromosome 1. Breeding and testing of reciprocal congenic lines confirmed the chromosome 1 LORR/BECRR QTL. A series of recombinant congenic sub-lines were bred to fine-map this QTL. Current results have narrowed the QTL to an interval of between 5 and 20 Mb. We expect to be able to narrow the interval to less than 5 Mb with additional genotyping and continued breeding of recombinant sub-congenic lines.

Quantitative trait loci for sensitivity to acute ethanol and ethanol consummatory behaviors in rats

“…; Radcliffe et al, 2009). In contrast to the TPT, however, IAT rats are more sensitive for ST and BECRR than IANT rats (Radcliffe et al, 2009). This finding suggests an at least partial genetic dissociation of LORR and TPT (for further discussion, see: Radcliffe et al, 2004b; Radcliffe et al, 2009).…”

“…The IAT/IANT rats also differ in ST and BECRR following a high dose EtOH injection (3.5 g/kg, i.p. ; Radcliffe et al, 2009). In contrast to the TPT, however, IAT rats are more sensitive for ST and BECRR than IANT rats (Radcliffe et al, 2009).…”

“…In contrast to the TPT, however, IAT rats are more sensitive for ST and BECRR than IANT rats (Radcliffe et al, 2009). This finding suggests an at least partial genetic dissociation of LORR and TPT (for further discussion, see: Radcliffe et al, 2004b; Radcliffe et al, 2009). Interestingly, a highly signicant quantitaive trait locus (QTL) was mapped for TPT at the same locus as the IAT/IANT F2 LORR QTL, though it was for the baseline TPT measure, not for the TPT response to EtOH (Radcliffe et al, 2009).…”

Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

“…A number of studies have demonstrated that ethanol-induced ataxia is genetically mediated in rodents [ 182 , 183 , 184 , 185 ]. These ataxia tests typically involve administering low to moderate doses of ethanol and then measuring variables such as latency to fall from a screen (screen test), number of foot slips on a wire mesh floor (grid test) or balance beam (balance beam test), or latency to fall from a fixed or rotating dowel (dowel test, rotarod test; see [ 174 ]).…”

“…Mice and rats have a righting reflex that corrects the orientation of their body when taken out of its normal, upright position. Given that ethanol is a central nervous system depressant that produces sedative–hypnotic effects on behavior, LORR can be used to estimate hypnotic sensitivity to ethanol in rodents and has been shown to be genetically influenced [ 83 , 85 , 108 , 182 , 183 , 185 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 ]. The LORR paradigm entails injecting animals with an anesthetic dose of ethanol, placing them on their backs in a V-shaped trough, and recording the amount of time it takes to regain the righting reflex as well as BEC at recovery [ 85 ].…”