Table 2.
In vitro and in vivo experiments using HNK treatment.
| Publication | Test Subject | Study Design | Antidepressant-Like Effect | Molecular Mechanism |
|---|---|---|---|---|
| Zanos et al. 2016 [69] | Male and female C57/BL6J mice | KET: female and male mice (FST) Ketamine metabolites: male mice (CSD, FST, ST) |
KET: Female mice > male mice HNK: HNK > (2S,6S)-hydroxynorketamine HNK: lacks ketamine-related side effects |
HNK-effects independent of NMDAR-signalling by AMPAR-signalling |
| Yamaguchi et al. 2018 [70] | Male C57/BL6 mice | LPS with (R)-ketamine and HNK (FST, TST) | (R)-ketamine > HNK Blocking CYP: (R)-ketamine effects ↑ |
(R)-ketamine and HNK in plasma, brain, CSF |
| Chou et al. 2018 [72] | Male and female Sprague-Dawley rats | LH with ketamine metabolites (FST, SPT) | HNK: Male ≈ Female (2S,6S)-hydroxynorketamine: no effect |
HNK: enhancement of AMPAR-signalling in vlPAG |
| Pham et al. 2018 [73] | Male BALB/cJ mice | Local (mPFC) and systemic injection of KET and HNK (FST) | Local injection: HNK ≈ KET Systemic injection: HNK ≈ KET |
HNK+KET: extracellular 5-hydroxytryptamine (mPFC) ↑, extracellular glutamate (mPFC) ↑ KET: extracellular GABA ↑ |
| Cavalleri et al. 2018 [74] | Murine and human DA neurons | KET and HNK in vitro | - | HNK+KET: structural plasticity ↑ (arborization ↑, soma size ↑) |
| Collo et al. 2018 [75] | Human DA neurons (PSCs) | KET and HNK in vitro | - | HNK+KET: structural plasticity ↑ (dendrite length ↑ and number ↑) |
| Yao et al. 2017 [76] | Male C57/BL6 mice | KET and HNK tested ex vivo with electrophysiology | - | HNK+KET: lasting modulation of AMPAR and synaptic plasticity (NAc+VTA), potentiation ↓ and depression ↑ of GA synapses (NAc+VTA-DA neurons) |
| Shirayama et al. 2018 [77] | Male Sprague-Dawley rats | LH with ketamine metabolites (CAT) | KET: antidepressant-like effect HNK: no effect |
- |
| Yang et al. 2017 [78] | Male C57/BL6 mice | LH and CSD with KET and HNK (FST, TST, SPT) | KET: antidepressant-like effect HNK: no effect |
- |
We list relevant, HNK-associated publications with significant impact in the field. HNK (2R,6R)-hydroxynorketamine, KET (R,S)-ketamine, FST Forced Swim Test, CSD Chronic Social Defeat Model of Depression, ST Sociability Test, NMDAR N-methyl-D-aspartate receptor, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, LPS Lipopolysaccharide Model of Depression, TST Tail Suspension Test, CYP Cytochrom P 450 Enzyme, CSF Cerebrospinal Fluid, LH Learned Helplessness Model of Depression, SPT Sucrose Preference Test, vlPAG ventrolateral Periaqueductal grey, mPFC medial Prefrontal Cortex, GABA gamma-aminobutyric acid, DA dopaminergic, PSC pluripotent stem cell, NAc Nucleus Accumbens, VTA Ventral Tegmental Area, GA glutamatergic, CAT Conditioned Avoidance Test.