海马-前额叶皮层谷氨酸能投射在成瘾记忆提取中的作用及机制

Craving and drug consumption will be retrieved once the addicts are re-exposed to the context previously associated with the drug of abuse after months, even years of abstinence. Given the fact that the associative memory for the psychological effects of addictive drugs and drug-related cues is firmly stored in patients' brain, one main mechanism for relapse is the memory retrieval by re-exposure to drug associated context. Studies have shown that the prefrontal cortex was significantly activated when drug addicts were exposed to drug-related environmental cues. Furthermore, systemic or local hippocampal administration of D1R antagonists could block the retrieval of short-term memory induced by environmental cues associated with morphine. However, the key brain regions, neural circuits, and synaptic and molecular events encoding short-/long-term drug addictive memory retrieval remain unclear. We speculate that the hippocampal D1R may mediate the addictive memory retrieval induced by environmental cues by activating hippocampus-prefrontal cortex (PFC) glutamatergic projection. Based on animal model of opiate addictive memory, commonly used morphine-induced conditioned place preference, we plan to investigate in this syudy: ① Changes of the hippocampal D1R level and hippocampal-PFC excitatory synaptic efficacy after the short- and long- term memory retrieval in rats; ② The effect of D1R-mediated cAMP-PKA signaling pathway on the synaptic efficacy; ③ The critical brain regions and neural circuits encoding short- and long- term addictive memory retrieval by using behavioral tests.

药物成瘾者停药后数月甚至数年内，一旦再次暴露于先前用药环境可诱发其再次用药的心理渴求和/或用药行为（即复吸）。复吸的主要机制之一是药物滥用期间，药物的精神效应与用药相关线索之间建立的联合型记忆被牢固储存于患者脑内，再次暴露于用药环境时该记忆便被激活或提取所致。研究已证明，药物成瘾者暴露于用药环境线索其前额叶皮层被明显激活；系统或海马给予D1R拮抗剂也能阻断环境线索诱发的吗啡成瘾短时记忆的提取，而编码长时成瘾记忆的提取的关键脑区、神经环路、突触与分子机制仍不清楚。我们推测海马内D1R可能通过激活海马-前额叶皮层的谷氨酸能投射而介导用药环境线索诱发的成瘾记忆的提取。本课题计划在动物阿片成瘾记忆模型上检测：① 成瘾记忆提取时海马D1R水平、海马-兴奋性突触效能的改变；② D1R介导的cAMP-PKA信号通路对该突触效能的影响；③ 行为学验证编码短时和长时成瘾记忆提取的关键脑区及环路机制。

随着成瘾性药物的滥用，药物的精神效应和用药相关环境线索之间可形成一种牢固的联合性记忆  药物成瘾记忆。药物成瘾记忆的巩固需要时间依赖性的海马与皮层间的相互作用，但潜在的机制仍不清楚。本项目研究海马CA1区多巴胺Ⅰ型受体（D1R）和CA1-背内侧前额叶皮层（dorsal medial prefrontal cortex, dmPFC）的谷氨酸能投射在吗啡成瘾记忆近期 (recent) 和远期 (remote) 提取中的作用及初步机制。主要结果如下：1）吗啡成瘾记忆近期提取时CA1区多巴胺D1R膜蛋白水平上调，D1R参与吗啡成瘾记忆近期提取，但不影响远期提取；2）dmPFC同时参与吗啡成瘾记忆的近期和远期提取。基于近期和远期提取后dmPFC内AMPAR受体亚基GluR1和GluR2膜蛋白表达水平不同（近期提取时GluR2膜蛋白上调，远期提取时GluR1和GluR2膜蛋白下调），我们推测dmPFC在吗啡成瘾记忆近期和远期提取中所起的作用不同。3）特异性交叉抑制海马CA1-dmPFC 传递可抑制吗啡成瘾记忆的近期提取，不影响远期提取。4）逆行示踪结果显示CA1到 dmPFC没有直接的纤维联系，近期提取后dSUB-dmPFC通路投射神经元活化程度显著高于远期提取，提示dSUB可能是CA1到dmPFC的中继核团。