Reward devaluation and heroin escalation is associated with differential expression of CRF signaling genes

• Heroin SA behavior is associated with differential CRF signaling gene expression.
• mRNA expression differences occur in memory, reward and executive brain systems.
• Differential mRNA expression of CRH binding protein may be regulated, in part, by CpG methylation.
• The NAc is striking in having no changes in mRNA expression in CRF signaling genes.
• Alignment of mPFC and Hipp may reflect coordinate CRF signaling in SA behavior.

One of the most damaging aspects of drug addiction is the degree to which natural rewards (family, friends, employment) are devalued in favor of seeking, obtaining and taking drugs. We have utilized an animal model of reward devaluation and heroin self-administration to explore the role of the coricotropin releasing factor (CRF) pathway. Given access to a saccharin cue followed by the opportunity to self-administer heroin, animals will parse into distinct phenotypes that suppress their saccharin intake (in favor of escalating heroin self-administration) or vice versa. We find that large saccharin suppressors (large heroin takers) demonstrate increased mRNA expression for elements of the CRF signaling pathway (CRF, CRF receptors and CRF binding protein) within the hippocampus, medial prefrontal cortex and the ventral tegmental area. Moreover, there were no gene expression changes of these components in the nucleus accumbens. Use of bisulfite conversion sequencing suggests that changes in CRF binding protein and CRF receptor gene expression may be mediated by differential promoter methylation.