For example, CX614 and LY451646 are high-impact agents, and CX1739 and Org26575 are low-impact agents. In addition, there is evidence that AMPA receptor potentiating agents have antidepressant actions in behavioral models as well as cellular targets of treatment response.87,88 Other than the in vitro studies of CX614 there is no direct evidence that AMPA receptor potentiating

drugs produce ketamine-like effects, such as activation of mTORC1 signaling and increased synaptogenesis. Further studies are required to determine if AMPA receptor potentiating agents influence these pathways and targets in vivo, and produce a rapid antidepressant response in models like CUS. While these Inhibitors,research,lifescience,medical novel targets, including AMPA receptor potentiating drugs and mGluR2/3 antagonists may prove to be rapid and effective antidepressant agents, it remains to be determined if they will also produce unwanted side effects. In addition, it is possible that the actions Inhibitors,research,lifescience,medical of these agents are closely

tied to synaptic levels of glutamate, since the efficacy of both depends on either blocking presynaptic glutamate actions Inhibitors,research,lifescience,medical at mGluR2/3 receptors, or potentiating postsynaptic actions of glutamate at AMPA receptors. Role of glycogen synthase kinase-3 (GSK-3) in the actions of ketamine: GSK-3 antagonists enhance the response to ketamine Another mechanism implicated in the actions of ketamine is regulation of GSK-3β. GSK-3β is a serine/threonine kinase that is inhibited by CI-1033 concentration lithium and is thought to play a significant role in the therapeutic actions of lithium in bipolar patients. Levels of GSK-3β are also increased in bipolar depressed patients.89 Inhibitors,research,lifescience,medical The function of GSK3 is inhibited by phosphorylation of specific amino acid residues. Interestingly, a recent study has demonstrated that ketamine Inhibitors,research,lifescience,medical increases the phosphorylation of these inhibitory

sites and that mice with a knockin of GSK-β that is resistant to phosphorylation do not show an antidepressant response to ketamine.90 These studies demonstrate that inhibition of GSK-3β significantly contributes to the actions of ketamine. This may occur in part by blocking the LTD-promoting actions of GSK-3β, which would enhance ketamine induction of the LTP-like synaptogenic effects (Figure 3). The interaction between ketamine and GSK-β inhibitors Oxymatrine is further demonstrated in a recent report. This study found that coadministration of ketamine and a selective GSK-3β inhibitor, SB216763, at low doses that have no effect when used alone, produce a significant antidepressant behavioral effect, as well as induction of mTORC1 signaling and synaptogenesis in the medial PFC.91 Similar effects were found with lithium, raising the possibility that ketamine plus lithium combination therapy could have reduced side effects compared with the higher dose of ketamine that is currently used.