NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required.
BACKGROUND
Relapse into drug abuse evoked by reexposure to the drug-associated context has been a primary problem in the treatment of drug addiction. Disrupting the reconsolidation of drug-related context memory would therefore limit the relapse susceptibility.


METHODS
Morphine conditioned place preference (CPP) was used to assess activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and correlative molecule expression in the Nucleus accumbens (NAc) shell during the reconsolidation of morphine CPP. U0126 and Arc/Arg3.1 antisense oligodeoxynucleotide were adapted to evaluate the role and the underlying mechanism of Arc/Arg3.1 during the reconsolidation.


RESULTS
The retrieval of morphine CPP in rats specifically increased the Arc/Arg3.1 protein level in the NAc shell, accompanied simultaneously by increases in the phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2), the phosphorylation of Cyclic Adenosine monophosphate (cAMP) response element-binding (pCREB), and the up-regulation of the membrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors GluR1 subunit level. Intra-NAc shell infusion U0126, an inhibitor of the Mitogen-activated protein kinase kinase (MEK), prevented the retrieval-induced up-regulation of pERK1/2, pCREB, Arc/Arg3.1, and membrane GluR1 immediately after retrieval of morphine CPP. The effect of disrupting the reconsolidation of morphine CPP by U0126 could last for at least 14 days, and could not be evoked by a priming injection of morphine. Furthermore, the specific knockdown of Arc/Arg3.1 in the NAc shell decreased the membrane GluR1 level, and impaired both the reconsolidation and the reinstatement of morphine CPP.


CONCLUSIONS
Arc/Arg3.1 in the NAc shell mediates the reconsolidation of morphine-associated context memory via up-regulating the level of membrane of GluR1, for which the local activation of the ERK-CREB signal pathway, as an upstream mechanism of Arc/Arg3.1, is required.
Neuroscience Research Institute, Peking University (Drs Lv, Sun, Cui, and Han); Department of Neurobiology, School of Basic Medical Sciences, Peking University (Drs Lv, Sun, Cui, and Han); Key Laboratory for Neuroscience of the Ministry of Education and the Ministry of Public Health, Beijing, China (Drs Lv, Sun, Cui, and Han); Basic Medical Research Centre, Medical School of Nantong University, Nantong, China (Dr Lv).
Xiu-Fang
XF
Lv
Neuroscience Research Institute, Peking University (Drs Lv, Sun, Cui, and Han); Department of Neurobiology, School of Basic Medical Sciences, Peking University (Drs Lv, Sun, Cui, and Han); Key Laboratory for Neuroscience of the Ministry of Education and the Ministry of Public Health, Beijing, China (Drs Lv, Sun, Cui, and Han); Basic Medical Research Centre, Medical School of Nantong University, Nantong, China (Dr Lv).
Lin-Lin
LL
Sun
Neuroscience Research Institute, Peking University (Drs Lv, Sun, Cui, and Han); Department of Neurobiology, School of Basic Medical Sciences, Peking University (Drs Lv, Sun, Cui, and Han); Key Laboratory for Neuroscience of the Ministry of Education and the Ministry of Public Health, Beijing, China (Drs Lv, Sun, Cui, and Han); Basic Medical Research Centre, Medical School of Nantong University, Nantong, China (Dr Lv) clcui@bjmu.edu.cn.
Cai-Lian
CL
Cui
Neuroscience Research Institute, Peking University (Drs Lv, Sun, Cui, and Han); Department of Neurobiology, School of Basic Medical Sciences, Peking University (Drs Lv, Sun, Cui, and Han); Key Laboratory for Neuroscience of the Ministry of Education and the Ministry of Public Health, Beijing, China (Drs Lv, Sun, Cui, and Han); Basic Medical Research Centre, Medical School of Nantong University, Nantong, China (Dr Lv).
Ji-Sheng
JS
Han
D000818:Animals; D001522:Behavior, Animal; D002070:Butadienes / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008568:Memory / Q000502:physiology; D009020:Morphine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D009020:Morphine; D009419:Nerve Tissue Proteins; D009570:Nitriles; D018091:Receptors, AMPA; C113580:U 0126; C092069:activity regulated cytoskeletal-associated protein
Activity regulated cytoskeleton-associated protein/activity-regulated gene 3.1; GluR1; cAMP response element-binding protein; conditioned place preference; extracellular signal-regulated kinase; reconsolidation