Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats

Addiction to psychostimulants is associated with neuroadaptive changes in various brain regions. In this experiment we use a model of methamphetamine self-administration during which we use footshocks as adverse consequences to divide rats into animals that continue to press an active lever to get the drug (shock-resistant) whereas other rats stop or significantly reduce pressing the lever (shock-sensitive) in the presence of these adverse consequences. To investigate potential molecular bases for the divergent phenotype, we performed a whole rat transcriptome study using Affymetrix rat arrays that cover more than 24,000 coding transcripts. The array experiments revealed that there were 24 differentially expressed genes between the resistant and sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis revealed that these transcripts belong in a network of genes involved in nervous system development and function, cell signaling, behavior, and disorders of the basal ganglia. These genes included proenkephalin (PENK) and prodynorphin (PDYN), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms that impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats. Six rats from each of the 3 groups including control, shock resistant, and shock sensitive were selected based on RNA quality and integrity for RNA extraction and hybridization on Affymetrix microarrays.