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Striatal microRNA controls cocaine intake through CREB signalling

Abstract

Cocaine addiction is characterized by a gradual loss of control over drug use, but the 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 markedly amplifying the stimulatory effects of the drug on cAMP response element binding protein (CREB) signalling. This action occurs through miR-212-enhanced Raf1 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 indicate that striatal miR-212 signalling has a key role in determining vulnerability to cocaine addiction, reveal new 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 the modulation of noncoding RNAs.

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Figure 1: Increased striatal miR-212 expression in extended access rats.
Figure 2: Dissociable effects of striatal miR-212 on cocaine intake.
Figure 3: miR-212 amplifies CREB signalling.
Figure 4: miR-212 stimulates core CREB signalling components.
Figure 5: miR-212 amplifies CREB signalling through Raf1.
Figure 6: Striatal CREB–TORC signalling controls cocaine intake.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE21901.

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Acknowledgements

This work was supported by a grant from the National Institute on Drug Abuse (NIDA) to P.J.K. and C.W., and NIDA post-doctoral awards to J.A.H. and H.-I.I. We thank M. Fallahi-Sichani for help with miRNA expression analysis and T. Balla for the Raf1 expression constructs. We also thank C. Fowler and P. Griffin for comments on the manuscript, and NIDA for supplying the cocaine used in these studies. This is manuscript 19873 from Scripps Florida.

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Authors

Contributions

J.A.H., H.-.I.I., A.L.A., J.K., P.B. and Q.L. performed all experiments; D.W. performed microarray analysis; M.D.C. and C.W. provided essential reagents and advice; P.J.K. designed the molecular experiments; J.A.H. and P.J.K. designed the behavioural experiments, performed the statistical analyses and wrote the manuscript.

Corresponding author

Correspondence to Paul J. Kenny.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures.

This file contains Supplementary Figures 1-39 with legends. (PDF 2089 kb)

Supplementary Table 1. Supplementary Tables 1 and 2 were added on 04 August 2010

This file contains gene targets for miR-212 whose expression was knocked down. (DOC 191 kb)

Supplementary Table 2

This table contains the complete microarray data. (XLS 6404 kb)

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Hollander, J., Im, HI., Amelio, A. et al. Striatal microRNA controls cocaine intake through CREB signalling. Nature 466, 197–202 (2010). https://doi.org/10.1038/nature09202

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