杏仁核强啡肽/kappa阿片受体系统在吗啡戒断诱导的抑郁样行为中的作用及机制研究

The negative affective disorders including depression and anxiety following opiates withdrawal underlies the induction of psychological dependence and drug seeking behaviors. It has been well documented that dynorphin and its cognate κ opioid receptor plays an important role in the regulation of aversive emotion, activation of κ opioid receptor could induce significant depressive-like behaviors and conditioned place aversion. We have previously found that the depressive-like behaviors is induced following prolonged morphine abstinence, the administration of κ opioid receptor antagonist significantly blocked the depressive-like behaviors following morphine withdrawal, but the mechanism remains unclear. We recently verified the key role of κ opioid receptor in the development of depressive-like behaviors by showing that deletion of κ opioid receptor significantly abolished the depressive-like behaviors following morphine abstinence. We further found that the expression of prodynorphin and dynorphinA in the amygdala increased as well as p38 MAPK activation was induced accompanying with morphine withdrawal. Our preliminary data also show the expression of 5-HT transporter in the synaptic membrane increased significantly after morphine abstinence. The present study is aimed to firstly clarify the underlying mechanisms of κ opioid receptor modulated 5-HT system in the depressive-like behaviors following morphine abstinence. This study will make great contribution to exploring the mechanism of addiction and finding new drug targets for curing relapse.

阿片类药物戒断伴随的抑郁、焦虑等负性情绪是药物依赖者产生心理依赖和复吸的重要原因。强啡肽/kappa(κ)阿片受体系统参与情绪调控，激活κ阿片受体诱导动物产生抑郁，条件位置厌恶等负性情绪。我们前期研究发现吗啡成瘾动物戒断后表现出明显的抑郁样行为，κ受体抑制剂预处理可以阻断抑郁样行为的发生，调控机制尚不清楚。近期我们发现κ受体敲除小鼠在吗啡戒断后不表现明显的抑郁样行为，该结果证实了κ受体在吗啡戒断诱发抑郁样行为中的关键作用。我们还发现吗啡戒断诱导的抑郁样行为伴随杏仁核脑区强啡肽原和强啡肽A表达显著增加，p38丝裂原活化蛋白激酶 (p38 MAPK)发生激活。进一步研究发现杏仁核5-HT转运体在突触膜上表达显著增加。基于以上研究进展，我们将首次探讨强啡肽/κ受体系统与5-HT系统的关系及参与调控吗啡戒断诱导抑郁样行为的具体分子机制。本项目对于深入探索成瘾机制，寻找治疗复吸靶点具有重要意义。

阿片类药物戒断伴随的抑郁、焦虑等负性情绪是药物依赖者产生心理依赖和复吸的重要原因，但是其分子与神经环路机制目前尚不清楚。Kappa(κ)阿片受体系统参与情绪调控，其内源性激动剂是强啡肽，激活κ阿片受体诱导动物产生抑郁，条件位置厌恶等负性情绪。本项目旨在研究强啡肽/kappa(κ)阿片受体参与慢性吗啡戒断诱导抑郁样行为的分子和环路机制。我们发现慢性吗啡戒断上调杏仁核强啡肽/κ阿片受体系统功能，激活p38丝裂原活化蛋白激酶 ( p38 MAPK)，促进谷氨酸转运体1 (GLT1) 表达。抑制杏仁核κ受体, p38 MAPK和GLT1可显著阻断慢性吗啡戒断诱导的抑郁样行为。系统敲除κ受体可阻断慢性吗啡戒断诱导的抑郁样行为，p38 MAPK激活和GLT1表达增加，在杏仁核重新表达κ受体可恢复慢性吗啡戒断诱导的抑郁样行为，p38 MAPK激活及GLT1表达。. 杏仁核主要由锥体神经元组成，可投射至伏隔核，通过调控多巴胺的释放参与调控情绪。我们发现慢性吗啡戒断降低杏仁核锥体神经元兴奋性，抑制投射至伏隔核的谷氨酸能神经元末梢的钙释放，降低伏隔核神经元兴奋性。杏仁核脑区注射谷氨酸受体激动剂 S-AMPA, 增强杏仁核兴奋性突触传递可阻断慢性吗啡戒断诱导的抑郁样行为，并且可被伏隔核注射谷氨酸受体拮抗剂及多巴胺受体拮抗剂所抑制，伏隔核注射 D1 受体激动剂阻断抑郁样行为。提示杏仁核至伏隔核的谷氨酸能神经投射通过控制多巴胺释放影响慢性吗啡戒断诱导的情绪失调。进一步研究发现，激活杏仁核-伏隔核谷氨酸能神经投射阻断慢性吗啡戒断引起的抑郁样行为，可被伏隔核注射谷氨酸受体拮抗剂所阻断。进一步证明了杏仁核-伏隔核环路功能降低通过抑制多巴胺释放影响慢性吗啡戒断诱导的抑郁样行为。. 综上，我们得出结论，慢性吗啡戒断上调杏仁核强啡肽/kappa阿片受体功能，激活p38 MAPK, 上调GLT1表达，增加谷氨酸重摄取，抑制杏仁核-伏隔核谷氨酸能神经投射功能从而介导慢性吗啡戒断引起的抑郁样行为。项目所得结果对于阐明阿片类药物成瘾的分子机制，开发以GLT1和杏仁核-伏隔核为靶点的抗成瘾药物具有重要意义。