Striatal microRNA controls cocaine intake through CREB signalling

被引：311

作者：

Hollander, Jonathan A. ^{[1
]}

Im, Heh-In ^{[1
]}

Amelio, Antonio L. ^{[2
]}

Kocerha, Jannet ^{[3
,4
]}

Bali, Purva ^{[1
]}

Lu, Qun ^{[1
]}

Willoughby, David ^{[5
]}

Wahlestedt, Claes ^{[3
,4
]}

Conkright, Michael D. ^{[2
]}

Kenny, Paul J. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Mol Therapeut, Lab Behav & Mol Neurosci, Jupiter, FL 33458 USA

[2] Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA

[3] Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA

[4] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

[5] Ocean Ridge Biosci, Palm Beach Gardens, FL 33410 USA

来源：

NATURE | 2010年 / 466卷 / 7303期

关键词：

ADDICTION-LIKE BEHAVIOR; GENE-EXPRESSION; DORSAL STRIATUM; DRUG-ADDICTION; RAF INHIBITOR; ACTIVATION; SEEKING; BRAIN; NEUROPLASTICITY; PLASTICITY;

D O I：

10.1038/nature09202

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：197 / U66

页数：8

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