Key Laboratory of Chronobiology, Ministry of Health (Sichuan University), Sichuan University, Chengdu, PR China.
Brain Res. 2011 Oct 6;1416:26-34. doi: 10.1016/j.brainres.2011.07.045. Epub 2011 Jul 28.
Chronic morphine addiction may trigger functional changes in the mesolimbic dopamine system, which is believed to be the neurobiological substrate of opiate addiction. Brain derived neurotrophic factor (BDNF) has been implicated in addiction-related pathology in animal studies. Our previous studies have shown that RACK1 is involved in morphine reward in mice. The recent research indicates nuclear RACK1 by localizing at the promoter IV region of the BDNF gene and the subsequent chromatin modifications leads to the activation of the promoter and transcription of BDNF. The present study was designed to investigate if shRACK1 (a short hairpin RNA of RACK1) could reverse the mice's behavioral responses to morphine and BDNF expression in hippocampus and prefrontal cortex. No significant changes were observed in vehicle-infused mice which received no morphine treatment (CONC) and shRACK1-infused mice which received no morphine treatment (CONR), whereas vehicle-infused mice preceded the morphine injection (MIC) showed increased BDNF expression in hippocampus and prefrontal cortex, as compared to vehicle-infused mice which received no morphine treatment (CONC). Intracerebroventricular shRACK1 treatment reversed these, and in fact, ShRACK1-infused mice preceded the morphine injection (MIR) showed reduced BDNF expression in hippocampus and prefrontal cortex, as compared to MIC. In the conditioned place preference (CPP) test, inactivating RACK1 markedly reduces morphine-induced conditioned place preference. Non-specific changes in CPP could not account for these effects since general CPP of shRACK1- and vehicle-infused animals was not different. Combined behavioral and molecular approaches have support the possibility that the RACK1-BDNF system plays an important role in the response to morphine-induced reward.
慢性吗啡成瘾可能会引发中脑边缘多巴胺系统的功能变化，而该系统被认为是阿片成瘾的神经生物学基础。脑源性神经营养因子（BDNF）在动物研究中与成瘾相关的病理学有关。我们之前的研究表明，RACK1 参与了小鼠的吗啡奖赏。最近的研究表明，核 RACK1 通过定位于 BDNF 基因启动子 IV 区域并随后进行染色质修饰，导致启动子的激活和 BDNF 的转录。本研究旨在探讨 shRACK1（RACK1 的短发夹 RNA）是否可以逆转小鼠对吗啡的行为反应以及海马体和前额叶皮层中 BDNF 的表达。接受 vehicle 输注且未接受吗啡处理的小鼠（CONC）和接受 vehicle 输注且未接受吗啡处理的 shRACK1 输注的小鼠（CONR）没有观察到明显变化，但接受 vehicle 输注且接受吗啡注射的小鼠（MIC）与接受 vehicle 输注且未接受吗啡处理的小鼠（CONC）相比，BDNF 在海马体和前额叶皮层中的表达增加。脑室注射 shRACK1 逆转了这种情况，事实上，与 MIC 相比，接受 shRACK1 输注且接受吗啡注射的小鼠（MIR）BDNF 在海马体和前额叶皮层中的表达减少。在条件性位置偏好（CPP）测试中，抑制 RACK1 会显著减少吗啡诱导的条件性位置偏好。由于 shRACK1 和 vehicle 输注动物的 CPP 没有差异，因此非特异性 CPP 变化不能解释这些影响。结合行为和分子方法支持了 RACK1-BDNF 系统在对吗啡诱导的奖赏反应中起重要作用的可能性。
