Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11

H. M. Hood, P. Metten, J. C. Crabbe, K. J. Buck

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABAA receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABAA receptor γ2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for α1 subunit containing GABAA receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABAA receptor γ2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalGenes, Brain and Behavior
Volume5
Issue number1
DOIs
StatePublished - Feb 1 2006

Keywords

  • Alcohol
  • DBA/2J strain
  • GABA receptor
  • Haplotype
  • High resolution
  • Mouse
  • Pentobarbital
  • Zolpidem

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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