新型毒品氯胺酮成瘾记忆的神经环路基础

Ketamine, a new psychoactive substance, has strong psychological addiction effect and normal memory impairment effect. At the same time, ketamine is found as a good candidate of antidepressant. Moreover, the antidepressant effect of ketamine depend the intact of the circuits from the hippocampus (HP) to the prefrontal cortex (PFC), also named “HP-PFC circuits”. At present, ketamine has been abused by more and more adolescents. Psychological addiction is a kind of very stable memory on drug and related clues, which is called addiction memory. It is difficult to treat drug addiction just because of the long-lasting addiction memory of drug abusers and the higher possibility of relapse at any time. Scientists have found that addictive memory shares common molecular and circuit pathways with normal learning and memory. Our preliminary results indicated that the HP-PFC circuit would be one of the common circuits. Permanent disconnection of two of the subcircuits of the HP-PFC circuit (from the ventral or dorsal hippocampus to the medial prefrontal cortex) can prevent the formation of morphine addictive memory. But there are complex subcircuits between the two key cerebral cortical areas related with learning and memory. It was unknown on the roles of these subcircuits and the transmitter regulation mechanisms. Present plan is to study this theme, the HP-PFC circuit long-term synaptic plasticity and transmitter receptor roles in drug addiction by multiply methods, such as pharmacological, behavioral, electrophysiological techniques and IHC, etc. This work will help to clarify the circuit regulation mechanism of outside of the classic rewarding circuit and help for rational utilization of the antidepressant effect avoiding the side effect of psychological addiction.

新型毒品氯胺酮（KET）心理成瘾作用强，并损伤正常记忆，青少年滥用日益增多，但其又有很好的抗抑郁效果且此效果依赖海马(hippocampus, HP)-前额叶(prefrontal cortex, PFC)环路。心理成瘾本质是异常牢固的药物记忆，可称为成瘾记忆。本项目拟采用行为药理、电生理、免疫组化技术，通过对PFC、HP和HP-PFC环路在KET条件位置偏爱(CPP)中的作用及KET成瘾动物HP-PFC环路长时程突触可塑性的研究，确定HP-PFC环路如何参与KET成瘾，及其在成瘾记忆形成、表达和消退中是否和如何发挥作用；因HP不同亚区到PFC各亚区均有神经投射（HP-PFC亚环路），我们还将确定各亚环路是否和分别以何种方式参与成瘾记忆和正常记忆过程。回答以上问题将为阐明KET成瘾记忆的神经环路调控机制提供科学依据，并为合理利用KET的抗抑郁效果，避免成瘾性提供实验支持。

新型毒品氯胺酮（ketamine, KET）心理成瘾作用强，并损伤正常记忆和其他生理功能，在青少年滥用日益增多，但其又有很好的抗抑郁和一定神经保护、镇痛效果。且抗抑郁效果依赖海马(hippocampus, HP)-前额叶(prefrontal cortex, PFC)环路。本项目申请书的内容是拟采用行为药理、电生理、免疫组化技术，通过对PFC、HP和HP-PFC环路在KET条件位置偏爱(conditioned place preference, CPP)中的作用及KET成瘾动物HP-PFC环路长时程突触可塑性的研究，确定HP-PFC环路如何参与KET成瘾，及其在成瘾记忆形成、表达和消退中是否和如何发挥作用；因HP不同亚区到PFC各亚区均有神经投射（HP-PFC亚环路），我们还将确定各亚环路是否和分别以何种方式参与成瘾记忆和正常记忆过程。但由于多种原因，本项目所需的关键实验药品KET迟迟不能到位，故在2018-2020年期间，我们以非对称方式阻断腹侧海马（vHP）-杏仁体基底外侧核（basolateral amygdala, BLA）神经环路，发现被动回避记忆的巩固过程依赖该环路的完整性；同时发现吗啡成瘾消退小鼠vHP、PFC-EEG功率谱与消退方式相关，特别是γ和β频段。为KET成瘾环路的研究打下了基础。同时，还分别探讨了魔芋低聚甘露糖、红芸豆凝集素、鬼针草总黄酮等的神经行为效应研究，发现上述成分在认知（学习记忆）、情绪、免疫增强、肠道改善和神经保护方面具有一定改善作用，为生物活性成分的新用途开发和AD、抑郁症等的治疗提供了一定的实验证据。2020年9月后，我们在KET-CPP建立的基础上，采用化学遗传操作的方法探讨了HP、PFC及HP-PFC环路的在KET成瘾消退中的作用，发现ILa激活加快KET成瘾消退，ILa失活可减缓消退，该作用受PLa的负调控，且ILa失活会促进糖皮质激素的释放增加，BDNF水平降低。HP-PFC环路的具体功能研究尚在进行中。上述结果为阐明KET成瘾记忆的神经环路调控机制提供了一定的科学依据，并将为合理利用KET的抗抑郁效果，减少成瘾性提供