title: GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects.
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 NMDAR 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 h) 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.
authors.affiliation: Department of Biomedical Engineering, Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, IL 60201, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burgdorf
authors.forename: Xiao-lei
authors.initials: XL
authors.lastname: Zhang
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nicholson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Balster
authors.forename: J David
authors.initials: JD
authors.lastname: Leander
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Gross
authors.forename: Roger A
authors.initials: RA
authors.lastname: Kroes
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000627:therapeutic use; D020869:Gene Expression Profiling; D007649:Ketamine / Q000009:adverse effects*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009842:Oligopeptides; D017470:Receptors, Glutamate; D005473:Fluoxetine; D007649:Ketamine; C507283:GLYX-13 peptide