Quantitative trait loci mapping for ethanol sensitivity and neurotensin receptor density in an F2 intercross derived from inbred high and low alcohol sensitivity selectively bred rat lines.
BACKGROUND
Genetic variance in initial sensitivity to ethanol has been implicated as a risk factor for the development of alcoholism. Identification of the genes that confer differential initial sensitivity is an important goal for the development of new treatment strategies and for a comprehensive understanding of the mechanism of ethanol's action. Quantitative trait loci (QTL) mapping for initial sensitivity and other ethanol-related behavioral traits in model organisms has become an important first step for the ultimate identification of genes that contribute to variation in ethanol responses.


METHODS
An F(2) intercross was made from the Inbred High and Low Alcohol Sensitivity rat lines (IHAS and ILAS). The F(2) rats were tested for duration of the loss of righting reflex test (LORR); blood ethanol concentration at regain of righting reflex (BECrrr); BEC at the first time to reach criterion on the rotarod after 1.6 g/kg of ethanol (BEC1); acute functional tolerance on the rotarod (AFT); and high-affinity neurotensin receptor (NTR1) density in the nucleus accumbens (NAc), caudate putamen (CP), and ventral midbrain (VMB). A full genome scan with an average marker spacing of 16.8 cM for interval QTL mapping was conducted on the F(2) rats (N = 363).


RESULTS
Seven significant or suggestive QTL were detected for LORR, one for BECrrr, three for BEC1, two for NTR1 binding in the CP, and one for binding in the NAc, but none were mapped for AFT or NTR1 binding density in the VMB. Effect size of the seven LORR QTL, the trait for which the parental strains were selected, ranged from 3 to 4%, with all accounting for approximately 22% of the total phenotypic variation. One of the LORR QTL on chromosome 2 (approximately 87 cM) was significant, and a second QTL on chromosome 5 (approximately 37 cM) was suggestive for both LORR and BECrrr.


CONCLUSIONS
The results indicate that segregating populations derived from the IHAS and ILAS strains can be used for mapping ethanol sensitivity QTL. The chromosome 2 LORR QTL may confer variation in ethanol metabolism, whereas the chromosome 5 LORR/BECrrr QTL likely mediates central nervous system ethanol sensitivity. The small number or absence of QTL for BEC1, AFT, and NTR1 receptor density suggests that genetic variation for these traits is minimal in the IHAS/ILAS strains and/or the effect size of QTL for these traits is too small to be mapped efficiently in this sample of F(2) rats. The ultimate identification of genes underlying these alcohol sensitivity QTL will contribute to our understanding of the actions of alcohol in the central nervous system if not to a deeper understanding of the genetic risk factors for alcoholism.
Radcliffe
Richard A
RA
University of Colorado Health Sciences Center, Department of Pharmaceutical Sciences, Campus Box C238, 4200 East Ninth Avenue, Denver, CO 80262, USA. richard.radcliffe@uchsc.edu
Erwin
V Gene
VG
Draski
Laura
L
Hoffmann
Sarah
S
Edwards
Joel
J
Deng
Xin-Sheng
XS
Bludeau
Pequita
P
Fay
Tina
T
Lundquist
Kristy
K
Asperi
William
W
Deitrich
Richard A
RA
D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001947:Breeding / Q000379:methods; D002874:Chromosome Mapping / Q000379:methods*; D003433:Crosses, Genetic; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D008297:Male; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test / Q000379:methods; D013045:Species Specificity
D018028:Receptors, Neurotensin; D000431:Ethanol