Striatal microRNA controls cocaine intake through CREB signalling.
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.
Hollander
Jonathan A
JA
Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
Im
Heh-In
HI
Amelio
Antonio L
AL
Kocerha
Jannet
J
Bali
Purva
P
Lu
Qun
Q
Willoughby
David
D
Wahlestedt
Claes
C
Conkright
Michael D
MD
Kenny
Paul J
PJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000378:metabolism* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C519510:Crtc1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D035683:MicroRNAs; D014157:Transcription Factors; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D020930:MAP Kinase Kinase Kinases; D000262:Adenylyl Cyclases; D003042:Cocaine