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....

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Bibliographic Details
Published in:Nature (London) 2010-07, Vol.466 (7303), p.197-202
Main Authors: HOLLANDER, Jonathan A, IM, Heh-In, AMELIO, Antonio L, KOCERHA, Jannet, BALI, Purva, QUN LU, WILLOUGHBY, David, WAHLESTEDT, Claes, CONKRIGHT, Michael D, KENNY, Paul J
Format: Article
Language:English
Subjects:
Addictions
Addictive behaviors
Adenylyl Cyclases - metabolism
Adult and adolescent clinical studies
Animals
Behavior
Biological and medical sciences
Brain
Circuits
Cocaine
Cocaine - metabolism
Cocaine - pharmacology
Cocaine abuse
Cocaine-Related Disorders - drug therapy
Cocaine-Related Disorders - enzymology
Cocaine-Related Disorders - genetics
Cocaine-Related Disorders - metabolism
Control equipment
Corpus striatum
Cyclic AMP Response Element-Binding Protein - metabolism
Drug addiction
Drugs
Fundamental and applied biological sciences. Psychology
Genetic aspects
Intakes
Male
MAP Kinase Kinase Kinases - metabolism
Medical sciences
MicroRNA
MicroRNAs - biosynthesis
MicroRNAs - genetics
MicroRNAs - metabolism
Modulation
Molecular and cellular biology
Molecular genetics
Neostriatum - drug effects
Neostriatum - metabolism
Physiological aspects
Properties
Proto-Oncogene Proteins c-raf
Psychological aspects
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Rats
Rats, Wistar
Regulators
Reward
Rodents
Signal Transduction - drug effects
Signalling
Transcription Factors - metabolism
Transcription. Transcription factor. Splicing. Rna processing
Up-Regulation - drug effects
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Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature09202