**8. Noncoding RNA changes associated with drugs of abuse**

Given that most drug abuse research has focused on miRNAs, we will focus on this subclass. One approach to finding candidate addiction-related miRNAs is to examine miRNA expres‐ sion changes within brain regions implicated in addiction following varying levels of drug exposure. Using this approach, Hollander and colleagues [42] found that rats given extended (6 h/day), but not restricted (2 h/day), access to cocaine self-administration exhibited upregu‐ lation of miR-212 in the dorsal striatum, a region involved in establishing habitual behavior [43]. Since the extended access self-administration model produces a behavioral phenotype that mimics the escalation of drug intake observed in human drug addicts, the findings suggest that upregulated miR-212 may play a role in the development of compulsive drug taking. One gene target of miR-212 is MeCP2 [44], a protein whose increased expression in the NAc is associated with reductions in amphetamine reward CPP [17]. However in the dorsal striatum, decreases in MeCP2 via miR-212 regulation are associated with decreases in compulsive-like cocaine self-administration [44]. These findings highlight the importance of examining the roles of epigenetic modulators across different drug classes, brain regions, and drug abuse models.

Another approach to identify candidate miRNAs is through bioinformatics. Databases exist that identify predicted targets of miRNAs and their distribution within the brain. We recently identified miR-495 as a lead candidate that has targets enriched in the Knowledgebase of Addiction-Related Genes database [45] and exhibits high expression in the NAc [46]. We found that cocaine self-administration decreases levels of NAc miR-495 and increases expression of several addiction-related genes. These effects suggest that cocaine dysregulates NAc miR-495, leading to disinhibition of addiction-related gene expression.

miRNAs and other noncoding RNAs have also been implicated in brain changes observed with other drugs of abuse. Alcohol-dependent rats exhibit increases in miR-206 in the medial PFC (mPFC) [47], a brain region involved in executive control of drug-seeking behavior [48]. miR-206 directly targets and suppresses BDNF expression in the mPFC [47], where increases in BDNF in this region are associated with inhibiting motivation for cocaine [49, 50]. This suggests increases in miR-206 likely contribute to the development of alcohol dependency through suppression of BDNF. Additionally, several lncRNAs exhibit expression changes in the NAc of heroin addicts postmortem [51]. These promising findings suggest that noncoding RNAs provide a treasure trove of novel targets for regulating addiction-related gene changes and behaviors.
