title: Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine.
abstract: BACKGROUND
  Environmental enrichment alters susceptibility in developing drug addiction. We have demonstrated that rats raised in an enriched condition are more sensitive than rats raised in an impoverished condition to nicotine-induced locomotor activity, and this is associated with alterations of phosphorylated extracellular signal-regulated kinase 1/2 within the prefrontal cortex. This study determined the impact of microRNA-221 in the prefrontal cortex on phosphorylated extracellular signal-regulated kinase 1/2 and the enriched environment-dependent behavioral changes in response to nicotine.
  
  
  METHODS
  A microRNA array was conducted to profile microRNA expression in the prefrontal cortex of enriched condition and impoverished condition rats in response to repeated nicotine (0.35 mg/kg, s.c.) administration. microRNA-221 in the prefrontal cortex, nucleus accumbens, and striatum was further verified by quantitative real-time PCR. Lentiviral-mediated overexpression of microRNA-221 in PC12 cells and the medial prefrontal cortex was performed to determine the effects of microRNA-221 on nicotine-mediated phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated cAMP-response element-binding protein, and locomotor activity.
  
  
  RESULTS
  microRNA-221 was profoundly upregulated in the prefrontal cortex but not in nucleus accumbens and striatum of enriched condition rats relative to impoverished condition rats following repeated administration of nicotine. Overexpression of lentiviral-microRNA-221 attenuated nicotine-induced increase in phosphorylated extracellular signal-regulated kinase 1/2 in PC12 cells. Lentiviral-microRNA-221 overexpression in the medial prefrontal cortex further increased locomotor activity in impoverished condition but not in enriched condition rats in response to repeated nicotine administration. Accordingly, lentiviral-microRNA-221 attenuated nicotine-induced increases in phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated cAMP-response element-binding protein in the medial prefrontal cortex of impoverished condition but not enriched condition rats.
  
  
  CONCLUSIONS
  These findings suggest that environmental enrichment, via upregulation of prefrontal microRNA-221 expression, suppresses the nicotine-induced activation of extracellular signal-regulated kinase and cAMP-response element-binding protein, which provides a potential mechanism underlying enhanced locomotor sensitivity to nicotine.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Diego
authors.initials: D
authors.lastname: Altomare
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Sun
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Narasimha M
authors.initials: NM
authors.lastname: Midde
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Hao
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Michael
authors.initials: M
authors.lastname: Shtutman
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Jill R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu).
authors.forename: Kim E
authors.initials: KE
authors.lastname: Creek
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC (Dr Gomez, Dr Altomare, Dr Sun, Dr Middle, Mrs Ji, Dr Shtutman, Dr Turner, Dr Creek, and Dr Zhu). zhuj@sccp.sc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D050882:CREB-Binding Protein / Q000378:metabolism; D019295:Computational Biology; D004777:Environment; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D016716:PC12 Cells; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C576526:MIRN221 microRNA, rat; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine; D050882:CREB-Binding Protein
keywords: ERK; Environmental enrichment; medial prefrontal cortex; microRNA; nicotine