Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.
Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction.
Group of Cellular and Molecular Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain; IMIB (Murcia Institute of Biomedical Investigation), Murcia, Spain.
Daniel
D
García-Pérez
Roger
R
López-Bellido
Juana M
JM
Hidalgo
Raquel E
RE
Rodríguez
Maria Luisa
ML
Laorden
Cristina
C
Núñez
Maria Victoria
MV
Milanés
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D060565:Argonaute Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D035683:MicroRNAs / Q000187:drug effects* / Q000235:genetics; D009020:Morphine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
C582332:Ago2 protein, rat; D000701:Analgesics, Opioid; D060565:Argonaute Proteins; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase
Ago2; NAc; TH; VTA; miR-133b; morphine administration; morphine withdrawal