Figure 3.

Possible synaptic mechanisms of (2R,6R)- and (2S,6S)-hydroxynorketamine, according to [130]: (2R,6R)-HNK is believed to act on presynaptic terminals by increasing glutamate release, potentially through pathways that overlap with mGlu₂ signaling. This may occur as (2R,6R)-HNK reduces the inhibition of cAMP release induced by mGlu₂, or it may involve another mechanism driving glutamate release. The increased glutamate subsequently activates AMPA receptors (AMPAR), leading to the enhanced release of brain-derived neurotrophic factor (BDNF), activation of tropomyosin kinase B (TrkB) receptors, and the triggering of plasticity-related signaling pathways. These pathways include the upregulation of protein kinase B (AKT), extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), and mammalian/mechanistic target of rapamycin complex 1 (mTORC1), all of which promote protein synthesis, increase AMPAR expression, and support synapse formation, ultimately strengthening synaptic connections. Additionally, (2R,6R)-HNK may interfere with TrkB/AP-2 (Activator Protein-2) interactions, preventing TrkB endocytosis and stabilizing TrkB at the synapse. On the other hand, (2S,6S)-HNK moderately inhibits NMDA receptors (NMDARs) and might enhance intracellular signaling through an NMDAR inhibition-dependent mechanism, which includes the inhibition of eEF2 signaling, alongside increased AKT, ERK/MAPK, and mTORC1 activity.