Table 2.

Preclinical enantiomer-specific biological effects of (S)-ketamine and (R)-ketamine.

Prophylactic	(S)-ketamine	(2S,6S)-HNK did not prevent changes in AMPAR-mediated bursts in the CA3 [57]
		(2S,6S)-HNK prevented changes in NMDAR-related currents after chronic stress [57]
	(R)-ketamine	(2R,6R)-HNK prevented changes in AMPAR-mediated bursts in the CA3 [57]
		(2R,6R)-HNK prevented changes in NMDAR-related currents after chronic stress [57]
		An association was found between NFATc4s and (R)-ketamine’s behavioral prophylactic effects [61], mediated by changes in miR149 levels [62]
		Clianges in miR-132-5p, BDNF, MeCP2, TGF-β1, GluA1, and PSD-95 after chronic stress were prevented by (R)-ketamine [63]
		(R)-ketamine prevented central and systemic inflammation after LPS insult [69]
		(R)-ketamine prevented changes in gut microbiota composition after LPS insult [62]
Immediate	(S)-ketamine	mTORC1 inhibition blocked the antidepressant-like effects of (S)-ketamine [92]
		(S)-ketamine did not decrease inflammation [94–96]
		(S)-ketamine did not affect RANKL expression after chronic stress [100]
	(R)-ketamine	The antidepressant-like effects of (R)-ketamine were not affected by mTORC1 inhibition [92]
		MAPK inhibition blocked the immediate antidepressant-like effects of (R)-ketamine [92]
		Administration of (R)-ketamine increased levels of phosphorylated MAPK [92]
		The behavioral effects of (R)-ketamine + mGluR2/3 antagonists were mediated through BDNF-TrkB signaling [93]
		(R)-ketamine decreased inflammation via TrkB signaling [94–96]
		(R)-ketamine decreased RANKL expression after chronic stress [100]
		(R)-ketamine regulated TGF-β1 receptors, MAPKs, RANKL, and SERT differently than (S)-ketamine [101]
Sustained	(S)-ketamine	Repeated I.P. administration of (S)-ketamine rescued chronic stress-induced deficits in neuronal morphology, hippocampal LTP, GluA1, PSD-95, and Synapsin I through Rac-1-mediated synaptic plasticity [116]
		The sustained antidepressant-like effects of (S)-ketamine did not depend on TrkB activation [77]
	(R)-ketamine	The prolonged behavioral effects of (R)-ketamine were associated with increased dendritic spine density, synaptogenesis, and BDNF-TrkB signaling in hippocampus and PFC [119]
		The sustained behavioral effects of (R)-ketamine were associated with microglial ERK-NRBP1-CREB-BDNF signaling in the PFC [120]
		The sustained antidepressant-like effects of (R)-ketamine depended on TrkB activation [77,122]
		Upregulation of BDNF and AMPAR activity was associated with the sustained antidepressant-like effects of (R)-ketamine + an mGluR2/3 antagonist [77]

AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF: brain-derived neurotrophic factor; CREB: cyclic adenosine monophosphate response element-binding protein; ERK: extracellular signal-regulated kinase; HNK: hydroxynorketamine; I.P: Intraperitoneal; LPS: lipopolysaccharide; LTP: long-term potentiation; MAPK: mitogen-activated protein kinase; MeCP2: Methyl CpG binding protein 2; mGluR: metabotropic glutamate receptor; miRNA: microRNA; mTORC1: mechanistic target of rapamycin complex 1; NFATc4: nuclear factor of activated T cells 4; NMDAR: N-methyl-D-aspartate receptor; NRBP1: nuclear receptor binding protein 1; PFC: prefrontal cortex; PSD-95: postsynaptic density protein 95; RANKL: receptor activator of nuclear factor kB ligand; SERT: serotonin transporter; TGF-β1: transforming growth factor β1; TrkB: tropomyosin receptor kinase B.