title: Orexin A-mediated AKT signaling in the dentate gyrus contributes to the acquisition, expression and reinstatement of morphine-induced conditioned place preference.
abstract: Accumulating evidence indicates that the hippocampal dentate gyrus (DG), a critical brain region contributing to learning and memory, is involved in the addiction and relapse to abused drugs. Emerging studies also suggest the role of orexin signaling in the rewarding behavior induced by repeated exposure to opiates. In the present study, we investigated the dynamic adaptation of orexin signaling in the DG and its functional significance in the acquisition, expression, maintenance of and relapse to rewarding behavior induced by morphine. Repeated place conditioning with morphine significantly increased the orexin A content released from the lateral hypothalamic area projecting neurons into the DG. Local infusions of orexin A into the DG sensitized the acquisition of and relapse to the conditioned place preference induced by morphine. The application of the orexin receptor type 1 (OXR1) antagonist SB334867 significantly abolished the acquisition, expression and maintenance of the conditioned place preference induced by repeated exposure to morphine. Furthermore, the significant increase of the phosphorylation of AKT in the DG was associated with preference for the morphine-paired chamber in rats, which was reversed by the local administration of an OXR1 antagonist. Thus, these findings suggested that the dynamic upregulation of orexin A signaling, via the AKT pathway in the DG, may promote the acquisition and maintenance of opioid-induced craving behaviors and may increase sensitivity to the rewarding effect of subsequent opioids.
authors.affiliation: Department of Psychology, Guangzhou Medical University, China.
authors.forename: Sui-Jun
authors.initials: SJ
authors.lastname: Guo
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Psychology, Guangzhou Medical University, China.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Department of Psychology, Guangzhou Medical University, China.
authors.forename: Jin-Xiang
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001583:Benzoxazoles / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects* / Q000502:physiology; D003213:Conditioning, Psychological; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009287:Naphthyridines; D009293:Opioid-Related Disorders / Q000378:metabolism*; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000701:Analgesics, Opioid; D001583:Benzoxazoles; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D009020:Morphine; D014508:Urea; D051057:Proto-Oncogene Proteins c-akt
keywords: Morphine; orexin; reward