Gene expression differences in mice divergently selected for methamphetamine sensitivity.
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.
Palmer
Abraham A
AA
Columbia Genome Center, Columbia University, 1150 St. Nicholas Ave., New York, New York 10032, USA. aap2010@columbia.edu
Verbitsky
Miguel
M
Suresh
Rathi
R
Kamens
Helen M
HM
Reed
Cheryl L
CL
Li
Na
N
Burkhart-Kasch
Sue
S
McKinnon
Carrie S
CS
Belknap
John K
JK
Gilliam
T Conrad
TC
Phillips
Tamara J
TJ
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005819:Genetic Markers; D005838:Genotype; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D008811:Mice, Inbred DBA / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D040641:Quantitative Trait Loci; D012313:RNA / Q000235:genetics / Q000302:isolation & purification
D005819:Genetic Markers; D008694:Methamphetamine; D012313:RNA