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Gene expression differences in mice divergently selected for methamphetamine sensitivity

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Abstract

In an effort to identify genes that may be important for drug-abuse liability, we mapped behavioral quantitative trait loci (bQTL) for sensitivity to the locomotor stimulant effect of methamphetamine (MA) using two mouse lines that were selectively bred for high MA-induced activity (HMACT) or low MA-induced activity (LMACT). We then examined gene expression differences between these lines in the nucleus accumbens, using 20 U74Av2 Affymetrix microarrays and quantitative polymerase chain reaction (qPCR). Expression differences were detected for several genes, including Casein Kinase 1 Epsilon (Csnkle), glutamate receptor, ionotropic, AMPA1 (GluR1), GABA B1 receptor (Gabbr1), and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp-32). We used the www.WebQTL.org database to identify QTL that regulate the expression of the genes identified by the microarrays (expression QTL; eQTL). This approach identified an eQTL for Csnkle on Chromosome 15 (LOD=3.8) that comapped with a bQTL for the MA stimulation phenotype (LOD=4.5), suggesting that a single allele may cause both traits. The chromosomal region containing this QTL has previously been associated with sensitivity to the stimulant effects of cocaine. These results suggest that selection was associated with (and likely caused) altered gene expression that is partially attributable to different frequencies of gene expression polymorphisms. Combining classical genetics with analysis of whole-genome gene expression and bioinformatic resources provides a powerful method for provisionally identifying genes that influence complex traits. The identified genes provide excellent candidates for future hypothesis-driven studies, translational genetic studies, and pharmacological interventions.

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Acknowledgments

This work was supported by a generous gift from Judith P. Sultzberger, MD, NIH grants DA10913, AA07468, and MH70933, the National Association for Research on Schizophrenia and Depression, and grants from the Department of Veterans Affairs.

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Authors and Affiliations

  1. Columbia Genome Center, Columbia University, 1150 St. Nicholas Ave., New York, New York, 10032, USA

    Abraham A. Palmer, Miguel Verbitsky & Rathi Suresh

  2. Department of Genetics and Development, Columbia University, New York, New York, 10032, USA

    Rathi Suresh

  3. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, 97239, USA

    Helen M. Kamens, Cheryl L. Reed, Na Li, Sue Burkhart–Kasch, Carrie S. McKinnon, John K. Belknap & Tamara J. Phillips

  4. Portland Alcohol Research Center, Portland, Oregon, 97239, USA

    Helen M. Kamens, Cheryl L. Reed, Na Li, Sue Burkhart–Kasch, Carrie S. McKinnon, John K. Belknap & Tamara J. Phillips

  5. Research Service, Portland Veterans Affairs Medical Center, Portland, Oregon, 97239, USA

    John K. Belknap & Tamara J. Phillips

  6. Department of Human Genetics, University of Chicago, Chicago, Ilinois, 60637, USA

    T. Conrad Gilliam

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  1. Abraham A. Palmer
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Correspondence to Abraham A. Palmer.

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Palmer, A.A., Verbitsky, M., Suresh, R. et al. Gene expression differences in mice divergently selected for methamphetamine sensitivity. Mamm Genome 16, 291–305 (2005). https://doi.org/10.1007/s00335-004-2451-8

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