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Striatal microRNA controls cocaine intake through CREB signalling

Author

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  • Jonathan A. Hollander

    (Laboratory of Behavioral and Molecular Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Heh-In Im

    (Laboratory of Behavioral and Molecular Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Antonio L. Amelio

    (The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Jannet Kocerha

    (The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Purva Bali

    (Laboratory of Behavioral and Molecular Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Qun Lu

    (Laboratory of Behavioral and Molecular Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • David Willoughby

    (Ocean Ridge Biosciences, 10475 Riverside Drive, Palm Beach Gardens, Florida 33410, USA)

  • Claes Wahlestedt

    (The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Michael D. Conkright

    (The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

  • Paul J. Kenny

    (Laboratory of Behavioral and Molecular Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA)

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.

Suggested Citation

  • Jonathan A. Hollander & Heh-In Im & Antonio L. Amelio & Jannet Kocerha & Purva Bali & Qun Lu & David Willoughby & Claes Wahlestedt & Michael D. Conkright & Paul J. Kenny, 2010. "Striatal microRNA controls cocaine intake through CREB signalling," Nature, Nature, vol. 466(7303), pages 197-202, July.
    • Handle: RePEc:nat:nature:v:466:y:2010:i:7303:d:10.1038_nature09202
    DOI: 10.1038/nature09202
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