Striatal microRNA controls cocaine intake through CREB signalling

Abstract

Cocaine addiction is characterized by a gradual loss of control over drug use, but molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by dramatically amplifying the stimulatory effects of the drug on CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in determining vulnerability to cocaine addiction, reveal novel molecular regulators that control the complex actions of cocaine in brain reward circuitries, and provide an entirely new direction for the development of anti-addiction therapeutics based on modulation of noncoding RNAs.

Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17–producing T-helper cell differentiation

“…Expression of the miR-132/212 cluster is elevated in neurons and is tightly controlled by the transcription factor CREB (camp-response element binding protein) (34,35). miR-132 can amplify CREB activity, and stimulation of neuronal morphogenesis by CREB is abrogated by inhibition of miR-132 signaling, suggesting that CREB and miR-132 form a positive-feedback loop (36,37). Likewise, we show here that the miR-132/212 cluster is induced by AHR activation and amplifies AHR-mediated induction of T H 17 cells, suggesting that the miR-132/212 cluster and AHR may also form a positivefeedback loop.…”

Epigenetic Treatments for Cognitive Impairments

“…Similarly, in an animal model of drug addiction, prolonged experience with cocaine self-administration dramatically increased expression of miR-212 in the striatum (Hollander et al, 2010). However, in this case, this overexpression was associated with a dampening of the motivational properties of the drug by modulating CREB pathways linked to the stimulatory effects of cocaine.…”

Functions of microRNA in response to cocaine stimulation

“…Mattson et al (2005) show that cocaine may induce the phosphorylation activity of the transcription factor cAMP response element binding protein (CREB) by enhancing the functions of several downstream signal-related inter-cellular kinases. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on CREB signaling (Hollander et al, 2010). Acute exposure to cocaine singifcantly increases endothelin receptor type A (EDNRA) within 6-12 h (Pradhan et al, 2008).…”

“…Using rat as the animal model, we obtained the miRNA expression data GSE21901 (Hollander et al, 2010) in cocaine-treated rat dorsal striatum samples from the GEO (Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/) database (Edgar et al, 2002;Barrett et al, 2007Barrett et al, , 2011 to study the post-transcriptional regulatory mechanisms upon cocaine stimulation in vivo. Based on the NCode miRNAs microarray 474, data included three types of samples: 1) miRNA expression data collected 1 h after 0.5 mg/kg intravenous cocaine injection (restricted), 2) miRNA expression data collected 6 h after 0.5 mg/kg intravenous cocaine injection (extended), and 3) control group (not treated).…”

“…The mRNA expression data were obtained from miR-212 overexpression in the human HEK 293 cell line (Hollander et al, 2010), using the HG-U133_Plus_2 (Affymetrix Human Genome U133 Plus 2.0 Array) platform.…”