神经药理学报

神经药理学报 ›› 2018, Vol. 8 ›› Issue (5): 65-66.

• Session 4A: Drug Dependence and Abuse: Novel Targets and Mechanisms • 上一篇    下一篇

The Small GTPase Rac1 Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC

WANG Wei-sheng，JU Yun-yue，WANG Yu-jun，LIU Jing-gen   

  1. Key Laboratory of Receptor Research，Shanghai Institute of Materia Medica，Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science，Shanghai，201203，China
  • 出版日期:2018-10-26 发布日期:2018-11-16

The Small GTPase Rac1 Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC

WANG Wei-sheng，JU Yun-yue，WANG Yu-jun，LIU Jing-gen   

  1. Key Laboratory of Receptor Research，Shanghai Institute of Materia Medica，Chinese Academy of Sciences and Collaborative Innovation Center for Brain Science，Shanghai，201203，China
  • Online:2018-10-26 Published:2018-11-16

摘要： Aim：Extinction of aversive memories associated with drug withdrawal has been proposed as a therapeutic strategy for the treatment of drug addiction. However，the mechanisms underlying extinction of such memory are poorly understood. This study was，therefore，undertaken to investigate the role of Rho GTPase Rac1-mediated GABAAR endocytosis in the vmPFC in extinction of aversive memories associated with drug withdrawal. Methods：conditioned place aversion （CPA） was used as a model for measurement of the aversive memories of opiate withdrawal. Extinction experiments were performed as described in our previous study （Wang et al.，2012）. Results：we found that extinction of CPA required activation of Rac1 in the vmPFC in a brain-derived neurotrophic factor （BDNF）-dependent manner，which triggers actin polymerization via Pak1-cofilin signaling pathway，leading to synaptic localization of activity-regulated cytoskeleton-associated protein （Arc） in the vmPFC. The synaptic Arc further determines GABAA receptor（ GABAAR） endocytosis that is necessary and sufficient for vmPFC long-term potentiation and CPA extinction. Thus，extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABAAR endocytosis in the vmPFC，thereby suggesting therapeutic targets to promote extinction of the unwanted memory. Conclusion：BDNF dependent Rac1 GTPase activation in the vmPFC contributes to aversive memory extinction by Arc-mediated GABAA receptor
endocytosis.

关键词: conditioned place aversion, Rho GTPase Rac1, GABAAR endocytosis, extinction, BDNF

Abstract: Aim：Extinction of aversive memories associated with drug withdrawal has been proposed as a therapeutic strategy for the treatment of drug addiction. However，the mechanisms underlying extinction of such memory are poorly understood. This study was，therefore，undertaken to investigate the role of Rho GTPase Rac1-mediated GABAAR endocytosis in the vmPFC in extinction of aversive memories associated with drug withdrawal. Methods：conditioned place aversion （CPA） was used as a model for measurement of the aversive memories of opiate withdrawal. Extinction experiments were performed as described in our previous study （Wang et al.，2012）. Results：we found that extinction of CPA required activation of Rac1 in the vmPFC in a brain-derived neurotrophic factor （BDNF）-dependent manner，which triggers actin polymerization via Pak1-cofilin signaling pathway，leading to synaptic localization of activity-regulated cytoskeleton-associated protein （Arc） in the vmPFC. The synaptic Arc further determines GABAA receptor（ GABAAR） endocytosis that is necessary and sufficient for vmPFC long-term potentiation and CPA extinction. Thus，extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABAAR endocytosis in the vmPFC，thereby suggesting therapeutic targets to promote extinction of the unwanted memory. Conclusion：BDNF dependent Rac1 GTPase activation in the vmPFC contributes to aversive memory extinction by Arc-mediated GABAA receptor
endocytosis.

Key words: conditioned place aversion, Rho GTPase Rac1, GABAAR endocytosis, extinction, BDNF