title: In silico identification and in vivo validation of miR-495 as a novel regulator of motivation for cocaine that targets multiple addiction-related networks in the nucleus accumbens.
abstract: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression and are implicated in the etiology of several neuropsychiatric disorders, including substance use disorders (SUDs). Using in silico genome-wide sequence analyses, we identified miR-495 as a miRNA whose predicted targets are significantly enriched in the Knowledgebase for Addiction Related Genes (ARG) database (KARG; http://karg.cbi.pku.edu.cn). This small non-coding RNA is also highly expressed within the nucleus accumbens (NAc), a pivotal brain region underlying reward and motivation. Using luciferase reporter assays, we found that miR-495 directly targeted the 3'UTRs of Bdnf, Camk2a and Arc. Furthermore, we measured miR-495 expression in response to acute cocaine in mice and found that it is downregulated rapidly and selectively in the NAc, along with concomitant increases in ARG expression. Lentiviral-mediated miR-495 overexpression in the NAc shell (NAcsh) not only reversed these cocaine-induced effects but also downregulated multiple ARG mRNAs in specific SUD-related biological pathways, including those that regulate synaptic plasticity. miR-495 expression was also downregulated in the NAcsh of rats following cocaine self-administration. Most importantly, we found that NAcsh miR-495 overexpression suppressed the motivation to self-administer and seek cocaine across progressive ratio, extinction and reinstatement testing, but had no effect on food reinforcement, suggesting that miR-495 selectively affects addiction-related behaviors. Overall, our in silico search for post-transcriptional regulators identified miR-495 as a novel regulator of multiple ARGs that have a role in modulating motivation for cocaine.
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Bastle
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Oliver
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Gardiner
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Pentkowski
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bolognani
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Allan
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Chaudhury
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: M
authors.initials: M
authors.lastname: St Peter
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Galles
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Neisewander
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: N I
authors.initials: NI
authors.lastname: Perrone-Bizzozero
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics; D003042:Cocaine / Q000235:genetics / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000235:genetics*; D003198:Computer Simulation; D003216:Conditioning, Operant / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D009042:Motivation / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D020413:3' Untranslated Regions; C577768:MIRN495 microRNA, human; C547683:MIRN495 microRNA, mouse; D035683:MicroRNAs; D003042:Cocaine