TS–vMHb–cIPN神经环路在甲基苯丙胺复吸中的作用及机制研究

Methamphetamine (METH) has been one of most common abused drugs worldwide. To date, high rate of relapse is the greatest challenges in the treatment of drug addiction (including METH). However, the neural circuits and potential therapeutic targets underlying the development of METH-induced relapse behaviors remain poorly understood. Based on our previous research findings, combining optogenetics, patch clamp, fiber photometry and virus-dependent nervous tract-tracing techniques, METH self-administration (SA) mice model is used to investigate: ① role of cholinergic neurons in ventromedial habenula (vMHb) in METH-induced relapse-like behavior; ② role and targets of ‘triangular septum (TS)–vMHb–central core of the IPN (cIPN)’ circuit in regulating METH-induced relapse-like behavior; ③ effect of optogenetic manipulation of TS–vMHb–cIPN circuit on METH-induced relapse-like behavior. The findings of current study would contribute to understand the neuronal circuits and potential therapeutic targets underlying relapse to METH-seeking behaviors, and be benefit for the research and development of novel therapeutic approaches against relapse to METH.

甲基苯丙胺（Methamphetamine，METH）是常见毒品之一，其高复吸率是戒毒治疗的首要难题，目前，调控METH复吸的神经环路和靶点不明确，导致临床缺乏有效的戒毒干预手段。结合前期的研究工作基础，本项目拟建立小鼠METH自身给药模型，结合光遗传学、膜片钳、钙信号光纤记录、病毒依赖的神经束路追踪等技术，旨在探索：①腹内侧缰核（ventromedial habenula，vMHb）胆碱能神经元集群在METH复吸行为中的作用；②“三角隔核（Triangular septum，TS）–vMHb–脚间核中心部（central core of the IPN，cIPN）”神经环路在METH复吸行为中的作用和关键靶标；③光遗传学调控TS–vMHb–cIPN神经环路对METH复吸行为的影响。本项目的研究成果将有助于阐释调控METH复吸的神经环路和关键靶点，为防治复吸提供新靶标和新策略。

甲基苯丙胺（methamphetamine，METH）是世界主要滥用药物之一，具有极高的复吸率。然而，METH复吸的神经环路和分子靶标至今仍不清楚。首先，本项目采用METH诱发的小鼠条件化位置偏爱（conditioned place preference，CPP）模型，发现METH复燃激活三角隔核（triangular septum，TS）谷氨酸能神经元（TSGlu）和腹内侧缰核（ventromedial habenula，vMHb）胆碱能神经元（vMHbChAT）；分别抑制TSGlu、vMHbChAT均可阻断METH复燃行为。神经示踪发现TSGlu向vMHbChAT发出功能性直接投射，抑制TSGlu–vMHbChAT神经环路有效阻断METH复燃行为。METH复燃广泛增加vMHbChAT中谷氨酸受体表达，抑制NMDA受体可逆转METH priming导致的vMHbChAT过度激活。以上结果提示TSGlu–vMHbChAT是调控METH复吸的关键神经环路，且vMHbChAT中NMDA受体是关键分子靶标。此外，METH长期戒断增强小鼠焦虑样行为，伴随脚间核（interpeduncular nucleus，IPN）GABA能神经元（IPNGABA）过度激活；抑制IPNGABA显著缓解METH戒断期焦虑，提示IPNGABA是调控METH戒断综合征的关键脑靶标。本项目着重探究METH复吸及异常行为的关键脑靶标，有助于阐释中枢兴奋性药物的神经生物学机制，为研发成瘾治疗药物提供新思路。