Mapping of quantitative trait loci for ethanol preference in quasi-congenic strains

Vadász, Csaba; Saito, Mariko; Balla, Andrea; Király, István; Gyetvai, Beatrix; Mikics, Eva; Pierson, David J.; Brown, Donna; Nelson, James C.

doi:10.1016/s0741-8329(99)00068-3

Cited by 25 publications

(24 citation statements)

References 32 publications

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“…Univariate ANOVA across RQI strains indicated that genetic (between-strain) variation of alcohol consumption was highly significant for both the B6.Cb 5 i 7 (F 42,969 =5.59, p<0.001) and B6.Ib 5 i 7 (F 34,729 =7.37, p<0.001) inbred strain sets. Originally, two-bottle choice test data for B6.Cb 4 i 5 mice were analyzed as alcohol preference phenotype (14). For better comparability, these data were recalculated and are shown in Tables 1-2 as alcohol consumption (g·BW kg -1 ·day -1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Differences in alcohol drinking behavioral phenotypes between C57BL/6ByJ, BALB/cJ, CXBI/ByJ, progenitors and RQI strains have been reported previously (1,13,14). We developed a complex trait gene mapping strategy, Recombinant QTL Introgression, (15)(16)(17)(18)(19), which was applied to map QTLs on five chromosomes for alcohol preference and consumption in 80 RQI strains of the b 5 i 7 series (1).…”

Section: Introductionmentioning

confidence: 99%

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Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

et al. 2007

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One strategy to identify neurochemical pathways of addiction is to map the relevant genes. In the present study we used 43 B6.C and 35 B6.I inbred RQI mouse strains, carrying <3% donor genome on C57BL/6ByJ background, for gene mapping. The strains were phenotyped for consumption of alcohol (12% v/v) in a two-bottle-choice paradigm, and genotyped for 396 microsatellite markers. The current mapping study extends our earlier experiment scanning five mouse chromosomes (1) to a whole-genome study, and discusses the differences and limitations. Data were analyzed with composite interval (CIM) and multiple interval (MIM) QTL mapping methods. CIM of B6.C strains detected significant QTLs on chrs. 6 and 12. A suggestive, but not significant, locus was detected in the B6.I strains on chr. 12. The best MIM model for B6.C strains confirmed one QTL on chr. 6 and one QTL on chr. 12., while the MIM model for the B6.I strains confirmed the suggestive locus on chr. 12. Some of the QTLs for alcohol consumption are new, while others confirm previously reported QTLs for alcohol preference, and alcohol acceptance.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

et al. 2007

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“…The QTL for ethanolinduced sedation on chromosome 11 has been efficiently recombined away from the locus for AC1 during generation of lines (see Materials and Methods for details) and cannot contribute to the effects we described here (Bennett et al, 2002). In contrast, a QTL for ethanol consumption on chromosome 15 is linked to our 129/Sv-derived locus for AC8, and it is possible that the altered ethanol consumption in AC8 KO mice may be associated with the presence of a different gene associated with this QTL (Vadasz et al, 2000). This alternative is unlikely, because we demonstrated no difference in ethanol consumption between mice heterozygous at this locus compared with mice homozygous at this locus for 129/Sv sequences.…”

Section: Discussionmentioning

confidence: 99%

Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

et al. 2005

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The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA A receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.

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“…This eliminated the problem of genetic heterogeneity, which can lead to major errors in meta-analyses or any method of combining results across studies. This restriction led to the omission of only two mouse QTL studies of this trait, that of Gill et al (1998), using AXB/BXA recombinant inbred (RI) mice, and that of Vadasz et al (2000), using crosses between BALB/c and B6 mice. We found nine full-length, published studies in the literature meeting our criteria, eight of which reported independent data.…”

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The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies

2001

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On the basis of eight independent quantitative trait loci (QTL) studies of ethanol (alcohol) preference drinking in mice, a meta-analysis was carried out to examine the replicability of QTLs across studies and to enhance the power of QTL detection and parameter estimation. To avoid genetic heterogeneity, we analyzed only studies of mapping populations derived from the C57BL/6 (B6) and DBA/2 (D2) inbred progenitor strains. Because these studies were carried out in five different laboratories, there were substantial differences in testing procedure, data analysis, and especially in the choice of mapping population (BXD recombinant inbred strains, F2, backcross, selected lines, or congenic strains). Despite this, we found several QTLs that were sufficiently robust as to appear consistently across studies given the strengths and weaknesses of the mapping populations employed. These were on Chromosomes (Chrs) 2 (proximal to mid), 3 (mid to distal), 4 (distal), and 9 (proximal to mid). The P value for each of these QTLs, combined across all applicable studies, ranged from 10(-7) to 10(-15), with the additive effect of each QTL accounting for 3-5% of the trait variance extrapolated to an F2 population. Two other QTLs on Chrs 1 (distal) and 11 (mid) were less consistent, but still reached overall significance (P <.0001).

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Mapping of quantitative trait loci for ethanol preference in quasi-congenic strains

Cited by 25 publications

References 32 publications

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

Mapping of QTLs for Oral Alcohol Self-Administration in B6.C and B6.I Quasi-Congenic RQI Strains

Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies

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