Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways: Therapeutic Effects

Ketamine: NMDA Receptors and Beyond

“…Consistent with this idea, ketamine has been shown to persistently enhance AMPAR-mediated excitatory synaptic function in frontal cortex and hippocampus (Li et al, 2010;Autry et al, 2011;Nosyreva et al, 2013). These latter effects may result from different actions in different brain regions but appear to involve activation of the mechanistic target of rapamycin (mTOR) kinase, inhibition of eukaryotic elongation factor 2 kinase and enhanced signaling by BDNF through trk B receptors (Li et al, 2010;Autry et al, 2011;but see Murrough, 2016). Other work indicates that effects of ketamine on GABAergic interneurons in cortex may involve production of reactive oxygen species via NADPH oxidase (Behrens et al, 2007), whereas network effects of ketamine in the juvenile hippocampus involve nitric oxide synthase (Izumi and Zorumski, 2014).…”

“…At low micromolar concentrations, ketamine inhibits only a fraction of NMDARs (likely Ͻ50% block for most NMDAR subtypes at steady state under physiological conditions), leaving a significant percentage of NMDARs unblocked at peak drug effect (Dravid et al, 2007;Kotermanski et al, 2009). This latter point is important because prior studies indicate that the antidepressant-like effects of ketamine in rodents are not observed with anesthetic doses that block a higher fraction of NMDARs (Li et al, 2010). Furthermore, complete NMDAR block by high concentrations of ketamine also eliminates the complex effects of the drug on neuronal excitability and delayed metaplastic inhibition of LTP in the hippocampus of juvenile rats that are observed at low micromolar concentrations (Izumi and Zorumski, 2014).…”

“…Intriguingly, HNK, particularly 2R,6R-HNK, may also lack the psychosis-inducing properties of ketamine. This recent study pursues the fact that ketamine used in clinical practice in the United States is a mixture of R,S-enantiomers, and earlier studies found that R-ketamine has more potent antidepressant-like effects in rodents than S-ketamine , although the opposite is true at NMDARs (Liu et al, 2001). This enantioselectivity provides circumstantial evidence that NMDARs may not be the relevant trigger for antidepressant effects and prompted the focus on 2R,6R-HNK.…”

“…Importantly, the psychiatric effects of ketamine are observed at subanesthetic doses (Li et al, 2010;Abdallah et al, 2015) that likely achieve brain concentrations in the low micromolar range, although actual brain concentrations remain uncertain (Hartvig et al, 1995;Zhao et al, 2012). At low micromolar concentrations, ketamine inhibits only a fraction of NMDARs (likely Ͻ50% block for most NMDAR subtypes at steady state under physiological conditions), leaving a significant percentage of NMDARs unblocked at peak drug effect (Dravid et al, 2007;Kotermanski et al, 2009).…”

“…It is important to note that vacuolar changes induced by ketamine in rodents are observed at higher doses than antidepressant-like effects (40 mg/kg s.c. single dose vs 3-10 mg/kg i.p. single dose) (Olney et al, 1989;Li et al, 2010;Autry et al, 2011). Further complicating these observations is the uncertainty in estimating the concentrations of ketamine that are achieved in brain with various doses and administration routes.…”