Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction.
Cocaine is a highly addictive drug that exerts its effects by increasing the levels of released dopamine in the striatum, followed by stable changes in gene transcription, mRNA translation, and metabolism within medium spiny neurons in the striatum. The multiple changes in gene and protein expression associated with cocaine addiction suggest the existence of a mechanism that facilitates a coordinated cellular response to cocaine. Here, we provide evidence for a key role of miRNAs in cocaine addiction. We show that Argonaute 2 (Ago2), which plays an important role in miRNA generation and execution of miRNA-mediated gene silencing, is involved in regulation of cocaine addiction. Deficiency of Ago2 in dopamine 2 receptor (Drd2)-expressing neurons greatly reduces the motivation to self-administer cocaine in mice. We identified a distinct group of miRNAs that is specifically regulated by Ago2 in the striatum. Comparison of miRNAs affected by Ago2 deficiency with miRNAs that are enriched and/or up-regulated in Drd2-neurons in response to cocaine identified a set of miRNAs that are likely to play a role in cocaine addiction.
Schaefer
Anne
A
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA. aschaefer@mail.rockefeller.edu
Im
Heh-In
HI
Venø
Morten T
MT
Fowler
Christie D
CD
Min
Alice
A
Intrator
Adam
A
Kjems
Jørgen
J
Kenny
Paul J
PJ
O'Carroll
Donal
D
Greengard
Paul
P
D000818:Animals; D060565:Argonaute Proteins; D001921:Brain / Q000378:metabolism; D002470:Cell Survival; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D035683:MicroRNAs; D017447:Receptors, Dopamine D1; D003042:Cocaine