71 GLYX-13 enhances LTP in hippocampal slices,

demonstrating synaptic plasticity inducing effects of this agent. Recent studies DNA Synthesis pathway inhibitor demonstrate that GLYX-13 also produces a rapid antidepressant response in the CUS/anhedonia model of depression (Moskal J, personal communication). The potential of GLYX-13 is also supported by clinical studies. Representatives from Naurex, the company developing GLYX-13, have reported at a recent American College of Neuropsychopharmacology meeting (2012) that a single intravenous dose of GLYX13 produces a significant antidepressant response within 24 hours of treatment and that Inhibitors,research,lifescience,medical the effects last on average for 7 days. The cellular mechanisms Inhibitors,research,lifescience,medical underlying the actions of GLYX-13 are being examined. Although GLYX-13 is a partial agonist of the glycine site, it is also possible that it acts as a partial antagonist depending on the binding of endogenous glycine (ie, at higher levels of endogenous glycine, GLYX-13 could

antagonize binding) (Figure 3) . This would be consistent with the possibility that GLYX-13 increases glutamate transmission via blockade of tonic firing γ-aminobutyric acid (GABA) neurons (see below) and that the effects of GLYX-13 Inhibitors,research,lifescience,medical require AMPA receptor activation. Studies are currently underway to determine if GLYX-13 increases mTORC1 signaling, similar to the actions of ketamine. Ketamine stimulates a “glutamate burst”: metabotropic (mGluR) and AMPA receptors as rapid antidepressant targets The Inhibitors,research,lifescience,medical induction of synapse formation by ketamine, an NMDA antagonist, is unexpected as synaptic plasticity in cellular models of learning requires

NMDA receptor activation, not inhibition. Studies of glutamate transmission and regulation of GABA neurons have helped clarify this apparent paradox. Microdialysis studies demonstrate that ketamine administration causes a rapid (~ 30 minutes), but transient (~ 90 minutes) elevation of extracellular glutamate in the medial PFC.72 Inhibitors,research,lifescience,medical In addition, subsequent studies demonstrate that ketamine blocks the tonic firing of GABAergic interneurons, leading to the hypothesis that the glutamate burst results from disinhibition of glutamate terminals.73 These studies indicate that agents that increase glutamate release or act directly on postsynaptic AMPA receptors may also learn more have rapid-acting antidepressant effects. Several targets that could influence glutamate transmission are discussed. mGluR2/3 antagonists The metabotropic glutamate receptors (mGluRs) represent a diverse class that has been targeted for the treatment of depression as well as other psychiatric illnesses. There are eight different mGluR receptor subtypes that are divided into three major groups, with Group II receiving attention for the treatment of depression.