title: Essential role of the NO signaling pathway in the hippocampal CA1 in morphine-associated memory depends on glutaminergic receptors.
abstract: The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway has been reported to play a key role in memory processing. However, little is known about its role in drug-associated reward memory. Here, we report the following. 1) The NO pathway in the CA1 is critical for the retrieval of morphine-associated reward memory. Specifically, the nNOS, sGC and PKG protein levels in the CA1 were increased after the expression of morphine conditioned place preference (CPP). Intra-CA1 injection of an NOS, sGC or PKG inhibitor prevented morphine CPP expression. 2) The involvement of the NO pathway in morphine CPP requires NR2B-containing NMDA receptors (NR2B-NMDARs). NR2B-NMDAR expression was elevated in the CA1 following morphine CPP expression, and intra-CA1 injection of the NR2B-NMDAR antagonist Ro25-6981 not only blocked morphine CPP expression but also inhibited the up-regulation of nNOS, sGC and PKG. Moreover, the Ro25-6981-induced blockade of morphine CPP was abolished by intra-CA1 injection of a NOS substrate or an sGC activator. 3) The NR2B-NMDAR stimulated the NO pathway by up-regulating the phosphorylation of Akt(Ser473). Morphine CPP expression enhanced the pAkt(Ser473) level, which has been corroborated to regulate nNOS activity, and this effect was reversed by intra-CA1 injection of Ro25-6981. 4) GluR1 acted downstream of the NO pathway. The membrane level of GluR1 in the CA1 was increased after morphine CPP expression, and this effect was prevented by pre-injection of a PKG inhibitor into the CA1. Additionally, co-immunoprecipitation revealed an interaction between PKG and GluR1; this result further indicated a role of PKG in regulating GluR1 trafficking. Collectively, the results of our study demonstrated that the activation of the NR2B-NMDAR/NO/sGC/PKG signaling pathway is necessary for the retrieval of morphine-associated reward memory.
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Key Laboratory of Neuroscience, The Ministry of Education and the Ministry of Health, 38 Xueyuan Road, Beijing 100191, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Shen
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Key Laboratory of Neuroscience, The Ministry of Education and the Ministry of Health, 38 Xueyuan Road, Beijing 100191, PR China.
authors.forename: Xue-Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Key Laboratory of Neuroscience, The Ministry of Education and the Ministry of Health, 38 Xueyuan Road, Beijing 100191, PR China.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Ge
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Key Laboratory of Neuroscience, The Ministry of Education and the Ministry of Health, 38 Xueyuan Road, Beijing 100191, PR China.
authors.forename: Yi-Jing
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Department of Neurobiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China; Key Laboratory of Neuroscience, The Ministry of Education and the Ministry of Health, 38 Xueyuan Road, Beijing 100191, PR China. Electronic address: clcui@bjmu.edu.cn.
authors.forename: Cai-Lian
authors.initials: CL
authors.lastname: Cui
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009020:Morphine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017981:Receptors, Neurotransmitter; C069474:glutamine receptor; D009569:Nitric Oxide; D009020:Morphine; D051057:Proto-Oncogene Proteins c-akt
keywords: AMPAR; Hippocampal CA1 region; Morphine; NMDAR; Nitric oxide signaling pathway; Reward memory