Orexin A在下丘脑-海马通路介导吗啡成瘾中的作用及机制

A lot of research indicates that hippocampus plays an important role in morphine addiction. However, the mechanism remains largely unknown. It has been recently indicated that orexin neurons in the lateral hypothalamus (LH) project to hippocampus and contributes to addictive behavior, suggesting that orexin signaling in the hippocampus might be involved in morphine addiction. Our prior study found increased orexin A expression in the LH from the morphine addictive rats and intra-hippocampus injection of orexin-1 antagonist significantly inhibited morphine-induced long-term potentiation (LTP) and acquisition of conditioned place preference (CPP). We hypothesized that orexin synthesized in LH and released into the hippocampus plays a critical role in the synaptic plasticity relevant to morphine addiction. In the present project, we aim to investigate that: 1. whether orexin signaling in the hippocampus would be involved in morphine addiction; 2. whether orexin contributes to morphine addiction via facilitating hippocampus synaptic transmission; 3. the mechanisms underlying morphine-induced LTP in the hippocampus regulated by orexin. Our findings will advance our understanding of the role of orexin in addiction and lead to possible novel therapeutic targets.

大量研究表明海马在吗啡成瘾中发挥重要作用，但机制未明。研究显示下丘脑食欲素（orexin）神经元的激活参与了成瘾行为，且下丘脑外侧区orexin神经元有至海马的纤维投射，提示orexin可能通过作用于海马介导吗啡成瘾的形成。我们预实验发现吗啡成瘾大鼠下丘脑外侧区orexin A表达显著增高，且海马内注射orexin-1受体拮抗剂可显著抑制吗啡诱导的突触传递效率长时程增强和条件性位置偏爱（CPP）获得，因此我们设想：下丘脑可能通过促进orexin合成和分泌，调控海马突触传递从而参与吗啡成瘾。本项目拟从整体动物、海马切片以及细胞三个水平探讨：1. orexin是否通过作用于海马介导吗啡成瘾；2. orexin是否通过增强海马突触传递效率介导吗啡成瘾；3. orexin调节吗啡诱导海马突触传递效率增强的分子机制。本项目研究为防治吗啡成瘾提供新的作用靶点，具有重要临床和社会意义。

我们及同行的研究表明海马在吗啡成瘾中发挥重要作用，但机制仍不清楚。最新研究显示下丘脑orexin神经元的激活参与成瘾行为，且下丘脑外侧区orexin神经元有至海马的纤维投射，提示orexin可能通过作用于海马介导吗啡成瘾的形成。我们预实验显示吗啡成瘾大鼠下丘脑外侧区orexin A表达显著增高，且海马内注射orexin-1受体拮抗剂显著抑制吗啡诱导的突触传递效率长时程增强和条件性位置偏爱（CPP）获得。因此我们设想：下丘脑可能通过促进orexin合成和分泌，调控海马突触传递从而参与吗啡成瘾。本项目拟从整体动物，海马切片以及细胞三个水平探讨：1. orexin是否通过作用于海马介导吗啡成瘾；2. orexin是否通过增强海马突触传递效率介导吗啡成瘾；3. orexin调节吗啡诱导海马突触传递效率增强的分子机制。本项目的研究为防治吗啡成瘾提供新的作用靶点，具有重要的临床意义及巨大的社会价值。