%0 Journal Article %1 burgdorf2012glyx13 %A Burgdorf, J %A Zhang, X L %A Nicholson, K L %A Balster, R L %A David Leander, J %A Stanton, P K %A Gross, A L %A Kroes, R A %A Moskal, J R %D 2012 %J Neuropsychopharmacology %K antidepressant ketamine learned_helplessness %R 10.1038/npp.2012.246 %T GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects %U http://www.ncbi.nlm.nih.gov/pubmed?term=23303054 %X Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDA receptor glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/ kainate receptor activation as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 hr) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.Neuropsychopharmacology accepted article preview online, 3 December 2012; doi:10.1038/npp.2012.246.

@article{burgdorf2012glyx13, abstract = {Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDA receptor glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/ kainate receptor activation as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 hr) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.Neuropsychopharmacology accepted article preview online, 3 December 2012; doi:10.1038/npp.2012.246.}, added-at = {2013-01-15T13:59:17.000+0100}, author = {Burgdorf, J and Zhang, X L and Nicholson, K L and Balster, R L and David Leander, J and Stanton, P K and Gross, A L and Kroes, R A and Moskal, J R}, biburl = {https://www.bibsonomy.org/bibtex/20255b8664d76714bd1b3d24fef7f5179/kilianjay}, description = {GLYX-13, an NMDA Receptor Glycine-Si... [Neuropsychopharmacology. 2012] - PubMed - NCBI}, doi = {10.1038/npp.2012.246}, interhash = {57f20336f22d7433765be7240d491590}, intrahash = {0255b8664d76714bd1b3d24fef7f5179}, journal = {Neuropsychopharmacology}, keywords = {antidepressant ketamine learned_helplessness}, month = dec, pmid = {23303054}, timestamp = {2013-01-15T16:44:59.000+0100}, title = {GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects}, url = {http://www.ncbi.nlm.nih.gov/pubmed?term=23303054}, year = 2012 }