Changes in miRNAs in heroin self-administration

MicroRNAs (miRNA) are a class of non coding RNAs which modulate gene expression by binding to complementary sequence of target mRNA. Recently miRNAs have been attributed a role in neuroplasticity, learning and drug addiction. Heroin addiction is thought to induce long term neuroadaptative modifications in brain reward related areas but the role of miRNA in these modifications is unknown. To investigate this role, we have performed a genome-wide analysis on 736 mature miRNAs in rats self-administering heroin i.v. (SA). Rats acquired heroin SA under an FR1 schedule and were maintained under a FR5 schedule over 13 sessions, whereas control group was reinforced by i.v. saline. After extinction (15 days), rats were sacrificed and brains removed for the extraction of miRNAs from prefrontal cortex, n. accumbens (shell and core) and dorsal caudate-putamen (CPu). Analysis by RealTime-PCR revealed that heroin SA was associated to up-or down regulation of different miRNAs for each brain regions. The number of regulated miRNAs was maximal in the core (97 up- and 60 down-regulated) and in the CPu (106 up- and 21 down-regulated), and to a lesser extent in the prefrontal cortex (12 up- and 40 down-) and shell (25 up- and 16 down-). Changes in some miRNAs such as miR-34c, miR-301-a-3p, miR-122, miR-144, miR199a-5p, miR-298 and miR-217 were common to all 4 areas. We also studied miRNAs target genes and performed the expression profiling analysis by using specific RealTime primers. Disregulated target genes were Drd3 (DAD3receptors), Bdnf, Cckbr, Mecp2 and Nos1. These results suggest that some miRNAs are key regulators of the reward circuits and that they could be involved in the long term neuroadaptative modifications induced by heroin exposure