Gnao1 (G alphaO protein) is a likely genetic contributor to variation in physical dependence on opioids in mice.

Published

Journal Article

Chronic exposure to opioids leads to physical dependence, which manifests as the symptoms of drug withdrawal. Interindividual differences in withdrawal symptom severity are well known, and at least partially due to genetic variation. To identify genes contributing to variation in withdrawal severity, we chronically treated 30 strains of the AcB/BcA recombinant congenic mouse strain set, including their A/J and C57BL/6J (B6) progenitors, with morphine for seven days and compared jumping frequencies--a sensitive and widely used index of withdrawal magnitude--during naloxone-precipitated withdrawal (NPW). Jumping frequencies of B6 mice were more than threefold greater than values obtained in A/J mice. Visual inspection of the genomic distribution of parental haplotypes in the AcB/BcA strains identified a putative quantitative trait locus (QTL) localized to chromosome 8 (90-117 Mb), and this QTL was confirmed in a B6AF2 intercross. The most salient candidate gene within this QTL, Gnao1 (guanine nucleotide binding protein, alpha(o); G alpha(o); 96.3 Mb), was tested for functional relevance using quantitative PCR and an antisense oligodeoxynucleotide strategy. The expression of Gnao1 in the locus coeruleus was found to be upregulated in morphine-dependent B6 but not A/J mice. Antisense knockdown of Gnao1 reduced NPW jumping in B6, but not A/J, mice rendered dependent on either morphine or heroin, largely rescuing the original strain difference. These data strongly implicate the G alpha(o) protein in the locus coeruleus as contributing to interindividual variability in physical dependence on opioids in mice.

Full Text

Duke Authors

Cited Authors

  • Kest, B; Smith, SB; Schorscher-Petcu, A; Austin, J-S; Ritchie, J; Klein, G; Rossi, GC; Fortin, A; Mogil, JS

Published Date

  • September 15, 2009

Published In

Volume / Issue

  • 162 / 4

Start / End Page

  • 1255 - 1264

PubMed ID

  • 19460419

Pubmed Central ID

  • 19460419

Electronic International Standard Serial Number (EISSN)

  • 1873-7544

Digital Object Identifier (DOI)

  • 10.1016/j.neuroscience.2009.05.027

Language

  • eng

Conference Location

  • United States