PMID- 23303054
OWN - NLM
STAT- MEDLINE
DCOM- 20130917
LR  - 20220318
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 38
IP  - 5
DP  - 2013 Apr
TI  - GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces 
      antidepressant-like effects without ketamine-like side effects.
PG  - 729-42
LID - 10.1038/npp.2012.246 [doi]
AB  - 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.
FAU - Burgdorf, Jeffrey
AU  - Burgdorf J
AD  - Department of Biomedical Engineering, Falk Center for Molecular Therapeutics, 
      McCormick School of Engineering and Applied Sciences, Northwestern University, 
      Evanston, IL 60201, USA.
FAU - Zhang, Xiao-lei
AU  - Zhang XL
FAU - Nicholson, Katherine L
AU  - Nicholson KL
FAU - Balster, Robert L
AU  - Balster RL
FAU - Leander, J David
AU  - Leander JD
FAU - Stanton, Patric K
AU  - Stanton PK
FAU - Gross, Amanda L
AU  - Gross AL
FAU - Kroes, Roger A
AU  - Kroes RA
FAU - Moskal, Joseph R
AU  - Moskal JR
LA  - eng
GR  - NS044421/NS/NINDS NIH HHS/United States
GR  - R01 DA001442/DA/NIDA NIH HHS/United States
GR  - R43 MH071932/MH/NIMH NIH HHS/United States
GR  - R56 NS044421/NS/NINDS NIH HHS/United States
GR  - MH094835/MH/NIMH NIH HHS/United States
GR  - R01 NS044421/NS/NINDS NIH HHS/United States
GR  - R01 MH094835/MH/NIMH NIH HHS/United States
GR  - DA01442/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121205
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Antidepressive Agents)
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Oligopeptides)
RN  - 0 (Receptors, Glutamate)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 690G0D6V8H (Ketamine)
RN  - 6A1X56B95E (GLYX-13 peptide)
SB  - IM
MH  - Acoustic Stimulation/adverse effects
MH  - Action Potentials/drug effects
MH  - Animals
MH  - Antidepressive Agents/*therapeutic use
MH  - Brain/pathology
MH  - Conditioning, Operant/drug effects
MH  - Depression/*drug therapy/*physiopathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Excitatory Amino Acid Agonists/pharmacology/therapeutic use
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Exploratory Behavior/drug effects
MH  - Fluoxetine/therapeutic use
MH  - Gene Expression Profiling
MH  - Ketamine/*adverse effects
MH  - Long-Term Potentiation/drug effects
MH  - Male
MH  - Oligopeptides/*therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Glutamate/genetics/metabolism
MH  - Reflex, Startle/drug effects
MH  - Swimming/psychology
PMC - PMC3671991
EDAT- 2013/01/11 06:00
MHDA- 2013/09/18 06:00
PMCR- 2014/04/01
CRDT- 2013/01/11 06:00
PHST- 2013/01/11 06:00 [entrez]
PHST- 2013/01/11 06:00 [pubmed]
PHST- 2013/09/18 06:00 [medline]
PHST- 2014/04/01 00:00 [pmc-release]
AID - npp2012246 [pii]
AID - 10.1038/npp.2012.246 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2013 Apr;38(5):729-42. doi: 10.1038/npp.2012.246. Epub 
      2012 Dec 5.