Selective breeding, quantitative trait locus analysis, and gene arrays identify candidate genes for complex drug-related behaviors.
Acute functional tolerance to ethanol develops during a single exposure to ethanol; it has been suggested to be a predisposing factor for the development of ethanol dependence. Genetic determinants of acute functional tolerance, as well as of ethanol dependence, have been clearly demonstrated. We describe a novel approach that uses a combination of selective breeding (to segregate genes contributing to the phenotype of interest, i.e., acute functional tolerance to the incoordinating effect of ethanol), quantitative trait locus analysis (to define chromosomal regions associated with acute functional tolerance), and DNA microarray technology (to identify differentially expressed genes in the brains of the selected lines of mice) to identify candidate genes for the complex phenotype of ethanol tolerance. The results indicate the importance of a signal transduction cascade that involves the glutamate receptor delta2 protein, the Ephrin B3 ligand, and the NMDA receptor, as well as a transcriptional regulatory protein that may be induced by activation of the NMDA receptor (zinc finger protein 179) and a protein that can modulate downstream responses to NMDA receptor activation (peroxiredoxin), in mediating acute tolerance to the incoordinating effect of ethanol.
Tabakoff
Boris
B
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. boris.tabakoff@uchsc.edu
Bhave
Sanjiv V
SV
Hoffman
Paula L
PL
D020751:Alcohol-Induced Disorders / Q000235:genetics*; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001947:Breeding; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002874:Chromosome Mapping; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D040641:Quantitative Trait Loci / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D014157:Transcription Factors; D000431:Ethanol