BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model

Background: Preclinical studies have indicated that the ketamine metabolite ( 2R,6R )-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of ( 2R,6R )-HNK in a chronic restraint stress (CRS) mouse model.

Methods: C57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering ( 2R,6R )-HNK (10 mg/kg), a combination of ( 2R,6R )-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of ( 2R,6R )-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT–PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio.

Results: ( 2R,6R )-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, ( 2R,6R )-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of ( 2R,6R )-HNK were blocked by combinations with NBQX or ANA-12.

Conclusion: BDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of ( 2R,6R )-HNK in the CRS model of depression.