(2R,6R)-hydroxynorketamine improves PTSD-associated behaviors and structural plasticity via modulating BDNF-mTOR signaling in the nucleus accumbens.

Abstract

BACKGROUND:

Post-traumatic stress disorder (PTSD) is a mental illness caused by either experiencing or observing a traumatic event that is perceived to pose a serious risk to one's life. (2R,6R)-HNK has an alleviating effect on negative emotions, nevertheless, the mechanism of (2R,6R)-HNK action is unclear.

METHODS:

In this study, the single prolonged stress and electric foot shock (SPS&S) method was used to establish a rat model of PTSD. After determining the validity of the model, (2R,6R)-HNK was administered to the NAc by microinjection using a concentration gradient of 10, 50, and 100 μM, and the effects of the drug in the SPS&S rat model were evaluated. Moreover, our study measured changes in related proteins in the NAc (BDNF, p-mTOR/mTOR, and PSD95) and synaptic ultrastructure.

RESULTS:

In the SPS&S group, the protein expression of brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and PSD95 was reduced and synaptic morphology was damaged in the NAc. In contrast, after the administration of 50 μM (2R,6R)-HNK, SPS&S-treated rats improved their exploration and depression-linked behavior, while protein levels and synaptic ultrastructure were also restored in the NAc. With the administration of 100 μM (2R,6R)-HNK, locomotor behavior, and social interaction improved in the PTSD model.

LIMITATIONS:

The mechanism of BDNF-mTOR signaling after (2R,6R)-HNK administration was not explored.

CONCLUSION:

(2R,6R)-HNK may ameliorate negative mood and social avoidance symptoms in PTSD rats by regulating BDNF/mTOR-mediated synaptic structural plasticity in the NAc, providing new targets for the development of anti-PTSD drugs.

• Authors: Luping Gou, Yu Li, Shiqi Liu, Haohan Sang, Jiajun Lan, Jinhong Chen, Ling Wang, Changjiang Li, Bo Lian, Xianqiang Zhang, Hongwei Sun, Lin Sun
• Journal: Journal of affective disorders (J Affect Disord) Vol. 335 Pg. 129-140 (08 15 2023) ISSN: 1573-2517 [Electronic] Netherlands
• PMID: 37137411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• 6-hydroxynorketamine
• Brain-Derived Neurotrophic Factor
• Antidepressive Agents
• TOR Serine-Threonine Kinases
• mTOR protein, rat

Topics

• Rats
• Animals
• Nucleus Accumbens (metabolism)
• Brain-Derived Neurotrophic Factor (metabolism)
• Antidepressive Agents (pharmacology)
• Stress Disorders, Post-Traumatic (drug therapy)
• TOR Serine-Threonine Kinases (metabolism)
• Mammals (metabolism)