title: Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference.
abstract: Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV-miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations.
authors.affiliation: Division of Biochemistry, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors.forename: Vijay
authors.initials: V
authors.lastname: Chandrasekar
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing / Q000187:drug effects* / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: C509207:MIRN124 microRNA, human; C548144:MIRN124 microRNA, rat; C548145:MIRNLET7 microRNA, rat; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D003042:Cocaine