Brain-derived neurotrophic factor in the ventrolateral periaqueductal gray contributes to (2R,6R)-hydroxynorketamine-mediated actions.

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has recently been suggested as an ideal antidepressant for treating animal models of depression. However, its effects and mechanisms are subjects of debate. According to our recent studies, (2R,6R)-HNK not only acts as an antidepressant but also produces increased aggression by enhancing glutamatergic transmission in the ventrolateral periaqueductal gray (vlPAG). In the present study, we examined the contribution of brain-derived neurotrophic factor (BDNF) in the vlPAG to the actions of (2R,6R)-HNK. The systemic administration of a single dose of (2R,6R)-HNK produced antidepressant-like effects and increased aggression and further increased the levels of the BDNF protein in the vlPAG. Sustained BDNF RNAi-mediated knockdown or pharmacological inhibition of BDNF signaling in the vlPAG not only mimicked depression-like behaviors but also inhibited aggressive behaviors. The intra-vlPAG application of BDNF rapidly produced antidepressant-like effects and enhanced aggressive behaviors. Moreover, the vlPAG injection of a neutralizing BDNF antibody or the inhibition of BDNF signaling prior to the (2R,6R)-HNK application in the vlPAG blocked (2R,6R)-HNK-mediated actions. Furthermore, sustained vlPAG BDNF knockdown locally attenuated systemic (2R,6R)-HNK-mediated actions. In conclusion, BDNF in the vlPAG might play a role in regulating depression-like behaviors and aggressive behaviors. Moreover, BDNF in the vlPAG might be involved in the (2R,6R)-HNK-mediated antidepressant-like effects and increase in aggression. The present study further implicates a shared mechanism of BDNF and vlPAG signaling for antidepressant treatments and increased aggression.