1. Alcohol Clin Exp Res. 2004 Dec;28(12):1796-804.
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.
Radcliffe RA(1), Erwin VG, Draski L, Hoffmann S, Edwards J, Deng XS, Bludeau P,
Fay T, Lundquist K, Asperi W, Deitrich RA.
Author information:
(1)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
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.
PMID: 15608595 [PubMed - indexed for MEDLINE]
PUBMED: 15608595
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