Table 3: Summary of the effects of ketamine (2S,6S)-HNK, and (2R,6R)-HNK on neurotransmitter systems.
Key effects of ketamine and its (2R,6R)- and (2S,6S)-HNK metabolites discussed in this review are provided here. Notably, compared to ketamine, there is less knowledge regarding the effects of the HNKs on these neurotransmitter systems. (S) and (R) denote stereospecificity of the listed effect. PFC, prefrontal cortex; HPC, hippocampus; vlPAG, ventrolateral periaqueductal gray; DRN, dorsal raphae nucleus; NAc, nucleus accumbens; NR, nucleus reuniens; GP, globus pallidus; mGluR2/3, metabotropic glutamate receptor 2/3; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; 5-HT1B, serotonin receptor 1B; GAD67, glutamic acid decarboxylase 67.
| Drug | Neurotransmitter System |
||||
|---|---|---|---|---|---|
| Glutamate | GABA | Neurotrophin (BDNF) |
Opioid | Monoamine | |
| (R,S)-ketamine | NMDAR antagonist | Reduces extracellular GABA (PFC) | Increases expression (hippocampus) | (S) Full agonist at κ receptors | Increases serotonin (PFC,DRN) |
| Increases AMPAR activation | Reduces GAD67 expression | Increases release (cortical neurons) | (S) Partial agonist at μ receptors | (R) Increases norepinephrine (PFC) | |
| Increases extracellular glutamate (PFC) | Reduces parvalbumin expression | Structural enhancement of cortical and subcortical synapses | (R) Partial agonist at κ receptors | (S) Increases dopamine (PFC, NAc) | |
| Synergistic actions with mGluR2/3 antagonists | Binds and activates TrkB receptors | (R) Partial agonist at μ receptors | Increases 5-HT1B binding (HPC, NAc, GP, NR) | ||
| Increases VTA spontaneous firing | |||||
| (2R,6R)-HNK | Not a NMDAR antagonist at therapeutic concentrations | Increases release (cortical neurons) | Potential inverse agonist at μ and κ receptors | Increases serotonin (PFC) | |
| Synergistic actions with mGluR2/3 antagonists Increases AMPAR activation | Increases expression (vlPAG) | Increases norepinephrine (PFC) | |||
| Binds and activates TrkB receptors | |||||
| (2S,6S)-HNK | More potent NMDAR antagonist relative to (2R,6R)-HNK | Increases extracellular BDNF (PFC) | |||
| Lower affinity for TrkB relative to (2R,6R)-HNK | |||||