microRNA regulation related to the protective effects of environmental enrichment against cocaine-seeking behavior.
BACKGROUND
MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expression. Here we investigate miRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues.


METHODS
We conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of "high" and "low" cocaine seekers using a median split of cocaine-seeking behavior.


RESULTS
Differential expression analysis across high- and low-seekers identified 33 microRNAs that were differentially expressed in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity, neuronal signaling, and neuroinflammation signaling, and many are known addiction-related genes. Of the 33 differentially-expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking behavior.


CONCLUSION
These findings not only confirm the involvement of previously identified microRNAs (e.g., miR-212, miR-495) but also reveal novel microRNAs (e.g., miR-3557, miR-377) that alter, or are altered by, processes associated with cocaine-seeking behavior. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
['Vannan|Annika|A|', 'Powell|Gregory L|GL|', "Dell'Orco|Michela|M|", 'Wilson|Melissa A|MA|', 'Perrone-Bizzozero|Nora I|NI|', 'Neisewander|Janet L|JL|']
D000818:Animals D016739:Behavior, Addictive D003042:Cocaine D019970:Cocaine-Related Disorders D003213:Conditioning, Psychological D066249:Craving D003463:Cues D058999:Drug-Seeking Behavior D004777:Environment D015870:Gene Expression D005786:Gene Expression Regulation D008297:Male D035683:MicroRNAs D009042:Motivation D009714:Nucleus Accumbens D051381:Rats D017207:Rats, Sprague-Dawley D012646:Self Administration
miRNA Gene expression Motivation Drug abuse Isolation stress Substance use disorders