甲基苯丙胺成瘾联合学习记忆细胞的发现及机制研究

Synthetic drugs, represented by methamphetamine, have become the most popular drugs in China instead of cocaine. However, neither effective target nor approved pharmacological therapeutic is available. Drug addiction is stubborn pathological learning and memory, with compulsive drug taking and seeking as core characteristics. Although cue-induced relapse remains even after long-term withdrawal in addicts, material foundations and neurobiological mechanisms of which have not yet been elucidated. This project is proposed to establish methamphetamine-induced compulsive self-administration, as well as associative learning and memory of visual clues and methamphetamine in rats. Meanwhile, using behaviors, optogenetics, tet-off system, electrophysiology, virus tracer and confocal laser, the project is proposed to discover associative memory cells in the amygdala (the dorsolateral amygdala and the central amygdala) and visual cortex, reveal their roles in methamphetamine addiction, clarify the structural and functional changes of interactive projections and synapsis, as well as material structural foundations and neurobiological mechanisms underlying cue-induce relapse. These researches mentioned above not only have important theoretical significance of understanding the neurobiological mechanisms of higher nervous activities and illustrating neurobiology mechanisms of drug addiction, but also will provide new clues and new ideas for interventions and treatments of methamphetamine relapse.

以甲基苯丙胺为代表的合成毒品已取代海洛因成为我国第一大毒品，然而目前没有理想的干预靶标和药物。药物成瘾是一种顽固的病理性学习记忆，核心特征为强迫性用药觅药。成瘾者即使在长期戒断后再度暴露于药物相关线索仍可诱发复吸。然而，药物相关线索诱发复吸的物质基础和神经生物学机制尚未阐明。本项目拟大鼠为研究对象，在递增性自身给药模型中建立视觉线索和甲基苯丙胺联合学习记忆，利用行为学、光遗传学、tet-off系统、电生理学、病毒示踪、激光共聚焦等技术，在杏仁核（BLA和CeA）和视觉皮层纹状区寻找联合记忆细胞，研究其对成瘾行为的影响；阐明两个脑区的交互投射在结构和功能上的变化，以及突触结构和功能的改变，从而揭示药物相关线索诱发复吸行为的物质结构基础和神经生物学机制。这不仅对于认识脑高级神经活动的神经生物学基础、阐明药物成瘾机制具有重要的理论意义，还有可能为干预和治疗甲基苯丙胺成瘾的复吸提供新线索和新思路。

以甲基苯丙胺为代表的合成毒品已取代海洛因成为我国第一大毒品，然而目前没有理想的干预靶标和药物。药物成瘾是一种顽固的病理性学习记忆，核心特征为强迫性用药觅药。成瘾者即使在长期戒断后再度暴露于药物相关线索仍可诱发复吸。然而，药物相关线索诱发复吸的物质基础和神经生物学机制尚未阐明。本项目成功建立了可用于后续联合记忆细胞标记及机制研究的小鼠自身给药行为学范式，在行为学上揭示了甲基苯丙胺成瘾联合学习记忆机制的存在。形成期伴随操作行为的视觉线索与甲基苯丙胺的联合学习记忆直接增强甲基苯丙胺+视觉线索（P < 0.001）、甲基苯丙胺自身（P < 0.001）诱发的用药动机，增强线索自身（P < 0.01）诱发的觅药动机；提示与感觉刺激的联合学习记忆相似，联合学习记忆对于药物和线索各自引起的反应具有双向的增强作用。巴甫洛夫联合学习通过增强甲基苯丙胺单一刺激诱发的用药动机，促进小鼠甲基苯丙胺自身给药的形成（P < 0.001）；且减慢甲基苯丙胺成瘾的环境消退过程（P < 0.05）。本项目为进一步发现成瘾联合学习记忆细胞，进而阐明甲基苯丙胺成瘾的联合学习记忆机制奠定了坚实的基础，有望揭示甲基苯丙胺成瘾难以戒除背后的神经生物学机制，对发现有效的治疗甲基苯丙胺成瘾防复吸干预措施具有重要的意义。