Regional Analysis of The Brain Transcriptome In Mice Bred For High And Low Methamphetamine Consumption

Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq data from selectively bred mice with high or low risk for voluntary MA intake to construct coexpression and cosplicing networks for differential risk. Three brain reward circuitry regions, the nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral midbrain (VMB), were explored. With respect to differential gene expression and wiring, the VMB was more strongly affected than either the PFC or NAc. Coexpression network connectivity was higher in the low line than the high line in the VMB, oppositely affected in the NAc, and little impacted in the PFC. Gene modules protected from the effects of selection may help to eliminate certain mechanisms from significant involvement in risk for MA intake. One such module was enriched in genes with dopamine-associated annotations. Overall, the data suggest that mitochondrial function and glutamate-mediated synaptic plasticity have key roles in the outcomes of selective breeding for high versus low levels of MA intake. We used mass selection procedures to generate the third replicate set of the MA high and low drinking lines. The originating population for these lines was a B6D2F2 (F2) cross, and methods were precisely as described for the replicate 1 and 2 lines. The founding population of 120 F2 mice (60 per sex; 53-56 days of age on the initial day of testing) was tested in a 2-bottle choice examination of water vs. MA intake. Brain tissue was obtained from experimentally naïve, non-MA exposed replicate 3 high and low line mice from second or later litters of generation S5.