MicroRNAs and Drug Addiction

Abstract

Drug addiction is considered a disorder of neuroplasticity in brain reward and cognition systems resulting from aberrant activation of gene expression programs in response to prolonged drug consumption. Non-coding RNAs (ncRNAs) are key regulators of almost all aspects of cellular physiology. MicroRNAs (miRNAs) are small (∼21-23 nucleotides) ncRNAs transcripts that regulate gene expression at the post-transcriptional level. Recently, miRNAs were shown to play key roles in the drug-induced remodeling of brain reward systems that likely drives the emergence of addiction. Here, we review evidence suggesting that one particular miRNA, miR-212, plays a particularly prominent role in vulnerability to cocaine addiction. We review evidence showing that miR-212 expression is increased in the dorsal striatum of rats that show compulsive-like cocaine-taking behaviors. Increases in miR-212 expression appear to protect against cocaine addiction, as virus-mediated striatal miR-212 overexpression decreases cocaine consumption in rats. Conversely, disruption of striatal miR-212 signaling using an antisense oligonucleotide increases cocaine intake. We also review data that identify two mechanisms by which miR-212 may regulate cocaine intake. First, miR-212 has been shown to amplify striatal cAMP response element binding protein (CREB) signaling through a mechanism involving activation of Raf1 kinase. Second, miR-212 was also shown to regulate cocaine intake by repressing striatal expression of methyl CpG binding protein 2 (MeCP2), consequently decreasing protein levels of brain-derived neurotrophic factor (BDNF). The concerted actions of miR-212 on striatal CREB and MeCP2/BDNF activity greatly attenuate the motivational effects of cocaine. These findings highlight the unique role for miRNAs in simultaneously controlling multiple signaling cascades implicated in addiction.

Keywords: MeCP2; cocaine; miR-212; miRNA.

Figure 1

The miR-212/132 gene cluster is located on chromosome 17 in humans, 10 in rats, and 11 in mouse. Shown are mouse/human miR-212 and miR-132 genes, with locations of CRE elements through which CREB can stimulate miR-212 and miR-132 transcription.

Figure 2

Overexpression of miR-212 in striatum reverses the motivational properties of cocaine in rats with extended but not restricted access to cocaine. (A) Striatal miR-212 overexpression reverses the long-term trajectory of cocaine-taking behavior in rats with extended access. (B) Disruption of miR-212 signaling in striatum, achieved by local infusion of a locked nucleic acid (LNA) modified antisense oligonucleotide against miR-212 (LNA-antimiR-212) increases cocaine intake in extended access. Reproduced with permission from (Hollander et al., 2010).

Figure 3

Knockdown of MeCP2 in striatum reverses the motivational properties of cocaine in rats with extended but not restricted access to cocaine. (A) Lentivirus-mediated knockdown of MeCP2 in the striatum reverses the escalating cocaine intake typically seen in rats with extended access to cocaine. (B) In contract, MeCP2 knockdown does not alter cocaine intake in rats with restricted daily access to the drug. Reproduced with permission from (Im et al., 2010).