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

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.

Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice / 中山大学学报(医学科学版)

ObjectiveTo investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice. MethodsSNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （n = 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms. ResultsCompared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG. ConclusionIntrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

(2R,6R)-hydroxynorketamine acts through GluA1-induced synaptic plasticity to alleviate PTSD-like effects in rat models.

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder with high morbidity and great social and economic relevance. However, extant pharmacotherapies of PTSD require long-term use to maintain effectiveness and have enormous side effects. The glutamatergic system, especially the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), is an important target of current research on the mechanism of PTSD. Postsynaptic AMPAR function and expression are known to be increased by (2R, 6R)-hydronorketamine (HNK), the primary metabolite of ketamine. However, whether (2R,6R)-HNK alleviates PTSD-like effects via AMPAR upregulation is yet to be known. In the present study, rats were exposed to single prolonged stress and electric foot shock (SPS&S). Afterwards, gradient concentrations of (2R,6R)-HNK (20, 50, and 100 µM) were administered by intracerebroventricular (i.c.v.) injection. Open field, elevated plus maze, freezing behavior, and forced swimming tests were used to examine PTSD-like symptoms. In addition, the protein levels of GluA1, BDNF and PSD-95 were analyzed using western blotting and immunofluorescence, and the synaptic ultrastructure of the prefrontal cortex (PFC) was observed by transmission electron microscopy. We found that (2R,6R)-HNK changed SPS&S-induced behavioral expression, such as increasing autonomous activity and residence time in the open arm and decreasing immobility time. Likewise, (2R,6R)-HNK (50 µM) increased GluA1, BDNF, and PSD-95 protein expression in the PFC. Changes in synaptic ultrastructure induced by SPS&S were reversed by administration of (2R,6R)-HNK. Overall, we find that (2R,6R)-HNK can ameliorate SPS&S-induced fear avoidance in rats, as well as rat cognates of anxiety and depression. This may be related to GluA1-mediated synaptic plasticity in the PFC.