TY - JOUR
T1 - (2R,6R)-hydroxynorketamine targeting the basolateral amygdala regulates fear memory
AU - Xu, Yuanyuan
AU - Yu, Zhenfei
AU - Chen, Si
AU - Li, Zhenlong
AU - Long, Xiting
AU - Chen, Mengxu
AU - Lee, Chau Shoun
AU - Peng, Hsien Yu
AU - Lin, Tzer Bin
AU - Hsieh, Ming Chun
AU - Lai, Cheng Yuan
AU - Chou, Dylan
N1 - Funding Information:
This research was supported by National Natural Science Foundation of China , China: NsFc: 82260704 for Dr. Chou, 82160238 for Dr. Xu, 82160271 for Dr. Chen, and 82160353 for Dr. Li; The Foundation of Guizhou province of China : Qiankehejichu-ZK[2021]-General-414 for Dr. Chen; Basic Research Program of Guizhou province of China: Qiankehe ZK[2021]-basic 417 for Dr. Xu; Zunyi Medical University, China : [2018]5772-026 for Dr. Chou, F-953 for Dr. Xu, [2018]5772-022 for Dr. Chen, and [2018]5772-016 for Dr. Li; MacKay Medical College, Taiwan : MMC-RD-111-1A-P001 for Dr. Chou. National Training Program of Innovation and Entrepreneurship for undergraduates, China : 202110661034 for Mr. Yu.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2023/3/1
Y1 - 2023/3/1
N2 - (2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, has been proposed as an ideal next-generation antidepressant due to its rapid-acting and long-lasting antidepression-relevant actions. Interestingly, recent studies have shown that (2R,6R)-HNK may have diverse impacts on memory formation. However, its effect on fear memory extinction is still unknown. In the present study, we assessed the effects of (2R,6R)-HNK on synaptic transmission and plasticity in the basolateral amygdala (BLA) and explored its actions on auditory fear memory extinction. Adult male C57BL/6J mice were used in this study. The extracellular electrophysiological recording was conducted to assay synaptic transmission and plasticity. The auditory fear conditioning paradigm was performed to test fear extinction. The results showed that (2R,6R)-HNK at 30 mg/kg increased the number of c-fos-positive cells in the BLA. Moreover, (2R,6R)-HNK enhanced the induction and maintenance of long-term potentiation (LTP) in the BLA in a dose-dependent manner (at 1, 10, and 30 mg/kg). In addition, (2R,6R)-HNK at 30 mg/kg and directly slice perfusion of (2R,6R)-HNK enhanced BLA synaptic transmission. Furthermore, intra-BLA application and systemic administration of (2R,6R)-HNK reduced the retrieval of recent fear memory and decreased the retrieval of remote fear memory. Both local and systemic (2R,6R)-HNK also inhibited the spontaneous recovery of remote fear memory. Taken together, these results indicated that (2R,6R)-HNK could regulate BLA synaptic transmission and plasticity and act through the BLA to modulate fear memory. The results revealed that (2R,6R)-HNK may be a potential drug to treat posttraumatic stress disorder (PTSD) patients.
AB - (2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, has been proposed as an ideal next-generation antidepressant due to its rapid-acting and long-lasting antidepression-relevant actions. Interestingly, recent studies have shown that (2R,6R)-HNK may have diverse impacts on memory formation. However, its effect on fear memory extinction is still unknown. In the present study, we assessed the effects of (2R,6R)-HNK on synaptic transmission and plasticity in the basolateral amygdala (BLA) and explored its actions on auditory fear memory extinction. Adult male C57BL/6J mice were used in this study. The extracellular electrophysiological recording was conducted to assay synaptic transmission and plasticity. The auditory fear conditioning paradigm was performed to test fear extinction. The results showed that (2R,6R)-HNK at 30 mg/kg increased the number of c-fos-positive cells in the BLA. Moreover, (2R,6R)-HNK enhanced the induction and maintenance of long-term potentiation (LTP) in the BLA in a dose-dependent manner (at 1, 10, and 30 mg/kg). In addition, (2R,6R)-HNK at 30 mg/kg and directly slice perfusion of (2R,6R)-HNK enhanced BLA synaptic transmission. Furthermore, intra-BLA application and systemic administration of (2R,6R)-HNK reduced the retrieval of recent fear memory and decreased the retrieval of remote fear memory. Both local and systemic (2R,6R)-HNK also inhibited the spontaneous recovery of remote fear memory. Taken together, these results indicated that (2R,6R)-HNK could regulate BLA synaptic transmission and plasticity and act through the BLA to modulate fear memory. The results revealed that (2R,6R)-HNK may be a potential drug to treat posttraumatic stress disorder (PTSD) patients.
KW - (2R,6R)-hydroxynorketamine
KW - Basolateral amygdala
KW - Fear memory extinction
KW - Long-term potentiation
KW - Spontaneous recovery
KW - Synaptic transmission
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UR - http://www.scopus.com/inward/citedby.url?scp=85144773470&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2022.109402
DO - 10.1016/j.neuropharm.2022.109402
M3 - Article
C2 - 36565854
AN - SCOPUS:85144773470
SN - 0028-3908
VL - 225
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 109402
ER -