Genomic Insights into Acute Alcohol Tolerance

  1. Wei Hu,
  2. Laura Saba,
  3. Katherina Kechris,
  4. Sanjiv V. Bhave,
  5. Paula L. Hoffman and
  6. Boris Tabakoff
  1. Departments of Pharmacology (W.H., L.S., S.V.B., P.L.H., B.T.) and Preventive Medicine and Biometrics (K.K.), University of Colorado School of Medicine, Aurora, Colorado
  1. Address correspondence to:
    Dr. Boris Tabakoff, Department of Pharmacology, University of Colorado School of Medicine, Mail Stop 8303, P.O. Box 6511, Aurora, CO 80045-0511. E-mail: boris.tabakoff{at}ucdenver.edu

Abstract

Alcohol “sensitivity” has been proposed as a predictive factor for development of alcohol dependence (Schuckit et al., 2005). Most measures of alcohol sensitivity in humans and animals include a component that can be ascribed to acute functional tolerance (AFT). AFT is a form of tolerance that develops within a single period of alcohol exposure and has a genetic component. We used microarray technology as well as quantitative trait locus analysis of phenotypic and gene expression data across 30 BXD recombinant inbred strains of mice, 20 inbred strains of mice, and two replicate lines of mice selectively bred for differences in AFT, to identify differentially expressed candidate genes that contribute to predisposition to AFT. Eight candidate genes were identified by our statistical and filtering methods. The location of brain expression of these genes was mapped using the Allen Brain Atlas (http://www.brain-map.org), and the transcript location and molecular pathway analysis indicated that brain structures and biochemical pathways implicated in long-term potentiation and memory might also participate in the generation of acute functional alcohol tolerance.

Footnotes

  • This work was supported in part by National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health (U01 AA016649-INIA Project; U01 AA016663-INIA Project; U01 AA013478-INIA Project; R24 AA013162-06A1) and the Banbury Fund.

  • Parts of this work were previously presented as follows: Wei H (2008) Genomic determinants of alcohol effects, Ph.D. thesis, University of Colorado, Denver, CO.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.137521.

  • ABBREVIATIONS: AFT, acute functional tolerance; SOA, sons of alcoholics; RI, recombinant inbred; HAFT, lines of mice selectively bred for high AFT; LAFT, lines of mice selectively bred for low AFT; QTL, quantitative trait locus; eQTL, expression QTL; BEC, blood alcohol concentration; SNP, single nucleotide polymorphism; FDR, false discovery rates; LOD, logarithm of the odds; bQTL, behavioral QTL; chr; chromosome; Wnk1 and Wnk1, WNK lysine-deficient protein kinase 1; GluR, glutamate receptor; NMDA, N-methyl-d-aspartate; Syt2 and Syt2, synaptotagmin 2; Cutl1 and Cutl1, cut-like 1 (Drosophila); Hlf and Hlf, hepatic leukemia factor; Mtch2, mitochondrial carrier homolog 2; Drd2 and Drd2, dopamine receptor D2; Drd3 and Drd3, dopamine receptor D3; Grm1 and Grm1, glutamate receptor, metabotropic 1; Kcnb1 and Kcnb1, voltage-gated potassium channel; Adora1 and Adora1, adenosine A1 receptor; Gria1 and Gria1, glutamate receptor, ionotropic, AMPA 1; Gria4 and Gria4, glutamate receptor, ionotropic, AMPA 4; Epb4.1l2 and Epb4.1l2, erythrocyte protein band 4.1-like 2; G protein, guanine nucleotide-binding protein.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received February 4, 2008.
    • Accepted June 9, 2008.
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  1. doi: 10.1124/jpet.108.137521 JPET September 2008 vol. 326 no. 3 792-800
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