Wenjin Xu1,2, Qingxiao Hong1,2, Zi Lin1, Hong Ma3, Weisheng Chen1,2, Dingding Zhuang1,2, Huaqiang Zhu1,2, Miaojun Lai1,2, Dan Fu1,2, Wenhua Zhou4,5, Huifen Liu6,7. 1. Laboratory of Behavioral Neuroscience, Ningbo Kangning Hospital, Ningbo Institute of Microcirculation and Henbane, School of Medicine, Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China. 2. Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, 315010, Zhejiang, People's Republic of China. 3. Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, 315201, Zhejiang, People's Republic of China. 4. Laboratory of Behavioral Neuroscience, Ningbo Kangning Hospital, Ningbo Institute of Microcirculation and Henbane, School of Medicine, Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China. whzhou@vip.163.com. 5. Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, 315010, Zhejiang, People's Republic of China. whzhou@vip.163.com. 6. Laboratory of Behavioral Neuroscience, Ningbo Kangning Hospital, Ningbo Institute of Microcirculation and Henbane, School of Medicine, Ningbo University, Ningbo, 315010, Zhejiang, People's Republic of China. liuhuifen91@163.com. 7. Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, 315010, Zhejiang, People's Republic of China. liuhuifen91@163.com.
Abstract
RATIONALE: Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. OBJECTIVE: This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. METHODS: MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1 day or 14 days after withdrawal from heroin self-administration. Following 14 days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. RESULTS: Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1 day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1 day, and meCP2 expression in NAc was higher after 14 days than after 1 day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. CONCLUSIONS: Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.
RATIONALE: Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. OBJECTIVE: This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. METHODS: MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1 day or 14 days after withdrawal from heroin self-administration. Following 14 days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. RESULTS: Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1 day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1 day, and meCP2 expression in NAc was higher after 14 days than after 1 day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. CONCLUSIONS: Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.
Authors: Wen G Chen; Qiang Chang; Yingxi Lin; Alexander Meissner; Anne E West; Eric C Griffith; Rudolf Jaenisch; Michael E Greenberg Journal: Science Date: 2003-10-31 Impact factor: 47.728
Authors: Mikko Airavaara; Charles L Pickens; Anna L Stern; Kristina A Wihbey; Brandon K Harvey; Jennifer M Bossert; Qing-Rong Liu; Barry J Hoffer; Yavin Shaham Journal: Addict Biol Date: 2010-12-23 Impact factor: 4.280