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Glutathione-S-transferase expression in the brain: possible role in ethanol preference and longevity

K. Björk^*,, S. T. Saarikoski, C. Arlinde, L. Kovanen, D. Osei-Hyiaman, M. Ubaldi^||, M. Reimers^¶, P. Hyytiä, M. Heilig^* and W. H. Sommer^*,,1

^* Laboratory of Clinical and Translational Studies, and

Laboratory of Physiologic Studies, NIAAA,

^¶ Laboratory of Molecular Pharmacology, NCI, National Institutes of Health, Bethesda, USA;

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;

Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland; and

^|| Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Italy

¹Correspondence: Laboratory of Clinical and Translational Studies, NIAAA/NIH, 10 Center Dr, B 10, R 15330, Bethesda, MD, USA. E-mail: wolfgang.sommer{at}mail.nih.gov

Identification of genes that are differentially expressed in rats bidirectionally selected for alcohol preference might reveal biological mechanisms underlying alcoholism or related phenotypes. Microarray analysis from medial prefrontal cortex (mPFC), a key brain region for drug reward, indicated increased expression of glutathione-S-transferases of the alpha (Gsta4) and mu (Gstm1–5) classes in ethanol-preferring AA rats compared with nonpreferring ANA rats. Real-time RT polymerase chain reaction (RT-PCR) analysis demonstrated 2-fold higher Gsta4 transcript levels in several brain regions of ethanol-naive AA compared with ANA rats. Differences in mRNA levels were accompanied by differential levels of GSTA4 protein. We identified a novel haplotype variant in the rat Gsta4 gene, defined here as var3. Allele frequencies of var3 were markedly different between AA and ANA rats, 52% and 100%, respectively. Gsta4 expression was strongly correlated with the gene dose of var3, with 60% of the variance in expression accounted for by genotype at this locus. The contribution of glutathione S-transferase expression to the ethanol-preferring phenotype is presently unclear. It could, however, underlie observed differences in life span between AA and ANA lines, prompting a utility of this animal model in aging research.—Björk, K., Saarikoski, S. T., Arlinde, C., Kovanen, L., Osei-Hyiaman, D., Ubaldi, M., Reimers, M., Hyytiä, P., Heilig, M. Sommer, W. H. Glutathione-S-transferase expression in the brain: possible role in ethanol preference and longevity.

Key Words: alcoholism • aging • animal model • microarray • haplotype

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