Adolescent cocaine experience differentially augments psychomotor sensitization in adulthood and alters dopamine receptor and epigenetic profiles in the nucleus accumbens of selectively bred high- and low-responder rats

Parsegian A, Garcia-Fuster J, Watson SJ, Flagel SB, Akil H
Society for Neuroscience. 2016.


Both genetic predisposition and environmental factors are thought to contribute to addiction liability. Early initiation of drug use in adolescence reliably predicts the likelihood of addiction in adulthood, but the molecular mechanism by which this occurs and whether genetic predisposition is involved is not known. Here we used a unique genetic model of two selectively bred rat lines that are known to differ in addiction liability to examine the impact of adolescent cocaine experience on psychomotor sensitization in adulthood and accompanying neurobiological alterations. Relative to bred low-responder (bLR) rats, bred high-responders (bHR) are typically more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking more readily following a prolonged period of abstinence. Consistent with previous findings, we found that only bHRs given a 7-day sensitizing regimen of cocaine (15 mg/kg) during adolescence (PND 33-39) showed psychomotor sensitization on day 7. However, adolescent cocaine history shifted the bLR phenotype to express sensitization in adulthood. By contrast, bHRs with adolescent cocaine history sustained the same levels of sensitization in adulthood as in adolescence. To further examine gene-by-environment interactions, we focused on certain epigenetic factors (i.e., chromatin modifications) that have been shown to influence genes, downstream signaling pathways, and proteins that have also been implicated in addiction liability. We found that two such histone modifications, acetylation (ac) and tri-methylation (me3) on histone 3 lysine 9 (H3K9) are altered in the ventral striatum following adolescent cocaine sensitization. We also developed a novel technique combining immunohistochemistry, in situ hybridization, and unbiased stereololgy to quantify these epigenetic modifications specifically in subregions of the nucleus accumbens (i.e., core and shell). In bHRs, we found that, relative to saline controls, adolescent cocaine exposure reduced the repressive mark H3K9me3 in the core and increased it in the shell, and reduced the permissive mark acH3K9 in the core. In bLRs, adolescent cocaine increased acH3K9 expression in the core, but not the shell, relative to their saline controls. We are currently determining whether these epigenetic changes occur more in certain striatal cell subtypes than others (e.g., D1 vs. D2). These results indicate that adolescent drug use can uniquely influence inborn genetic addiction liability via chromatin modifications in NAc dopamine neurons and promote subsequent drug sensitivity in adulthood.!/4071/presentation/23373