Guo Sui-Jun, Cui Yu, Huang Zhen-Zhen, Liu Huan, Zhang Xue-Qin, Jiang Jin-Xiang, Xin Wen-Jun
Department of Psychology, Guangzhou Medical University, China.
Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, China.
Addict Biol. 2016 May;21(3):547-59. doi: 10.1111/adb.12236. Epub 2015 Mar 10.
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.
越来越多的证据表明，海马齿状回（DG）作为对学习和记忆起关键作用的脑区，参与了药物成瘾及复吸过程。新兴研究还提示了食欲素信号传导在反复接触阿片类药物所诱导的奖赏行为中的作用。在本研究中，我们调查了DG中食欲素信号传导的动态适应性变化，及其在吗啡诱导的奖赏行为的获得、表达、维持及复吸方面的功能意义。吗啡反复位置条件化显著增加了从投射至DG的下丘脑外侧区神经元释放的食欲素A含量。向DG局部注入食欲素A可使吗啡诱导的条件性位置偏爱行为的获得及复吸变得敏感。应用1型食欲素受体（OXR1）拮抗剂SB334867可显著消除反复接触吗啡所诱导的条件性位置偏爱行为的获得、表达及维持。此外，DG中AKT磷酸化的显著增加与大鼠对吗啡配对室的偏爱有关，而局部给予OXR1拮抗剂可使其逆转。因此，这些发现提示，通过DG中的AKT通路，食欲素A信号传导的动态上调可能促进阿片类药物诱导的渴望行为的获得及维持，并可能增加对后续阿片类药物奖赏效应的敏感性。
