title: Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11.
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 GABA(A) 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 GABA(A) receptor gamma2 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 alpha1 subunit containing GABA(A) 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 GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.
authors.affiliation: Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR 97006-8921, USA. hoodh@ohsu.edu
authors.forename: H M
authors.initials: HM
authors.lastname: Hood
authors.forename: P
authors.initials: P
authors.lastname: Metten
authors.forename: J C
authors.initials: JC
authors.lastname: Crabbe
authors.forename: K J
authors.initials: KJ
authors.lastname: Buck
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D021122:Protein Subunits / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics*
chemical_list: C546280:Gabrg2 protein, mouse; D006993:Hypnotics and Sedatives; D021122:Protein Subunits; D011963:Receptors, GABA-A