Gene expression differences in mice divergently selected for methamphetamine sensitivity

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.

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…To our knowledge, the only selected lines that have been used to map an amphetamine-related trait are the HMACT and LMACT lines, bred for high and low sensitivity to the acute stimulant effects of methamphetamine. QTL analyses using DNA from mice of these lines provided evidence that there are genes that influence sensitivity to methamphetamine on chromosomes 5, 9, 11, 12, and 15 (Palmer et al, 2005). In an attempt to align possible differences in gene expression with genes that reside within these QTL regions, nucleus accumbens tissue from the HMACT and LMACT lines was used in a microarray gene expression analysis.…”

“…Because the mice were not methamphetamine-treated prior to brain biopsy, these differentially expressed genes represent innate genetic differences that might be expected to influence methamphetamine response. Of the genes found to be differentially expressed, some of them reside in the methamphetamine sensitivity QTL regions (Palmer et al, 2005). One that resides on chromosome 15 and was differentially expressed is casein kinase 1 epsilon (Csnk1e).…”

“…Genetic mouse models are being used to identify genes that may predict risk for the development of drug abuse and addiction. In particular, genetic mouse models have been used for estimating genetic correlations between drug-related traits , for studying the roles of specific genes in drug-relevant behavioral and biological traits (Crabbe et al, 2006;Cunningham and Phillips, 2003;Hall et al, 2004;Kieffer and Gaveriaux-Ruff, 2002;Laakso et al, 2002), and for addiction-related gene mapping Ferraro et al, 2005;Gill and Boyle, 2003;Janowsky et al, 2001;Palmer et al, 2005). The gene mapping work has the ultimate goal of gene identification and provision of genetic information relevant to complex human diseases, such as addiction (Phillips et al, 2002a).…”

“…For example, relatively few genetic studies have been aimed at amphetamine self-administration, using models that gauge the amount of effort an animal is willing to exert to obtain the drug, or place conditioning, which might provide information about genetic differences in sensitivity to drug-cue associations. Selective breeding procedures could be used to create lines that differ in rate or amount of amphetamine self-administered, followed by combined quantitative trait locus (QTL) and gene expression mapping to identify important genes (e.g., Palmer et al, 2005). More effort could be directed toward identifying mutants from N-ethyl-N-nitrosourea (ENU)-induced mutagenesis panels or transgenics that exhibit excessive intake or heightened risk for relapse.…”

Rapid Selection Response for Contextual Fear Conditioning in a Cross Between C57BL/6J and A/J: Behavioral, QTL and Gene Expression Analysis

“…A subset of these genes could be differentially expressed because there are cis-acting expression QTLs (eQTLs) located on these chromosomes causing the behavioral QTLs. We have previously used such evidence to implicate Csnk1e in methamphetamine response (Palmer et al 2005), and have gone on to show that this same gene is involved in human sensitivity to amphetamine (Veenstra-VanderWeele et al 2006). …”