PMID- 26210936
OWN - NLM
STAT- MEDLINE
DCOM- 20160614
LR  - 20181113
IS  - 1872-7549 (Electronic)
IS  - 0166-4328 (Print)
IS  - 0166-4328 (Linking)
VI  - 294
DP  - 2015 Nov 1
TI  - Rapastinel (GLYX-13) has therapeutic potential for the treatment of 
      post-traumatic stress disorder: Characterization of a NMDA receptor-mediated 
      metaplasticity process in the medial prefrontal cortex of rats.
PG  - 177-85
LID - S0166-4328(15)30110-8 [pii]
LID - 10.1016/j.bbr.2015.07.039 [doi]
AB  - Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial 
      agonist properties. It is a robust cognitive enhancer and shows rapid and 
      long-lasting antidepressant properties in both animal models and in humans. 
      Contextual fear extinction (CFE) in rodents has been well characterized and used 
      extensively as a model to study the neurobiological mechanisms of post-traumatic 
      stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry 
      in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, 
      studies were undertaken to examine the effects of rapastinel for its therapeutic 
      potential in PTSD and to use rapastinel as a tool to study its underlying 
      glutamatergic mechanisms. A 21-day chronic mild unpredictable stress (CUS) rat 
      model was used to model depression and PTSD. The effects of CUS alone compared to 
      No CUS controls, and the effects of rapastinel (3 mg/kg IV) on CUS-treated 
      animals were examined. The effect of rapastinel was first assessed using 
      CUS-treated rats in three depression models, Porsolt, sucrose preference, and 
      novelty-induced hypophagia tests, and found to produce a complete reversal of the 
      depressive-like state in each model. Rapastinel was then assessed in a 
      MPFC-dependent positive emotional learning paradigm and in CFE and again a 
      reversal of the impairments induced by CUS treatment was observed. Both synaptic 
      plasticity and metaplasticity, as measured by the induction of long-term 
      potentiation in rat MPFC slice preparations, was found to be markedly impaired in 
      CUS-treated animals. This impairment was reversed when CUS-treated rats were 
      administered rapastinel and tested 24 h later. Transcriptomic analysis of MPFC 
      mRNA expression in CUS-treated rats corroborated the link between rapastinel's 
      behavioral effects and synaptic plasticity. A marked enrichment in both the LTP 
      and LTD connectomes in rapastinel-treated CUS rats was observed compared to 
      CUS-treated controls. The effects of rapastinel on depression models, PEL, and 
      most importantly on CFE demonstrate the therapeutic potential of rapastinel for 
      the treatment of PTSD. Moreover, rapastinel appears to elicit its therapeutic 
      effects through a NMDA receptor-mediated, LTP-like, metaplasticity process in the 
      MPFC.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Burgdorf, Jeffrey
AU  - Burgdorf J
AD  - Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, 
      Northwestern University, 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
FAU - Kroes, Roger A
AU  - Kroes RA
AD  - Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
FAU - Zhang, Xiao-lei
AU  - Zhang XL
AD  - Department of Cell Biology & Anatomy, Basic Sciences Building, Rm. 217, New York 
      Medical College, Valhalla, NY 10595, USA.
FAU - Gross, Amanda L
AU  - Gross AL
AD  - Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
FAU - Schmidt, Mary
AU  - Schmidt M
AD  - Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
FAU - Weiss, Craig
AU  - Weiss C
AD  - Department of Physiology, Northwestern University Feinberg School of Medicine, 
      303 E. Chicago Avenue, Ward Building 7-140, Chicago, IL 6061, USA.
FAU - Disterhoft, John F
AU  - Disterhoft JF
AD  - Department of Physiology, Northwestern University Feinberg School of Medicine, 
      303 E. Chicago Avenue, Ward Building 7-140, Chicago, IL 6061, USA.
FAU - Burch, Ronald M
AU  - Burch RM
AD  - Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA.
FAU - Stanton, Patric K
AU  - Stanton PK
AD  - Department of Cell Biology & Anatomy, Basic Sciences Building, Rm. 217, New York 
      Medical College, Valhalla, NY 10595, USA.
FAU - Moskal, Joseph R
AU  - Moskal JR
AD  - Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, 
      Northwestern University, 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA; 
      Naurex Inc., 1801 Maple Ave., Suite 4300, Evanston, IL 60201, USA. Electronic 
      address: j-moskal@northwestern.edu.
LA  - eng
GR  - NS044421/NS/NINDS NIH HHS/United States
GR  - R01 NS059879/NS/NINDS NIH HHS/United States
GR  - R01 MH047340/MH/NIMH NIH HHS/United States
GR  - R56 MH047340/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  - NS059879/NS/NINDS NIH HHS/United States
GR  - MH47340/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150722
PL  - Netherlands
TA  - Behav Brain Res
JT  - Behavioural brain research
JID - 8004872
RN  - 0 (Excitatory Amino Acid Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (Psychotropic Drugs)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 6A1X56B95E (GLYX-13 peptide)
SB  - IM
MH  - Animals
MH  - Chronic Disease
MH  - Depressive Disorder/drug therapy/physiopathology
MH  - Disease Models, Animal
MH  - Excitatory Amino Acid Agents/pharmacology
MH  - Learning/drug effects/physiology
MH  - Long-Term Potentiation/drug effects/physiology
MH  - Male
MH  - Memory/drug effects/physiology
MH  - Oligopeptides/*pharmacology
MH  - Prefrontal Cortex/*drug effects/physiopathology
MH  - Psychotropic Drugs/*pharmacology
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Stress Disorders, Post-Traumatic/*drug therapy/physiopathology
MH  - Stress, Psychological
MH  - Tissue Culture Techniques
MH  - Transcriptome/drug effects/physiology
MH  - Uncertainty
PMC - PMC4702501
MID - NIHMS720144
OTO - NOTNLM
OT  - Depression
OT  - GLYX-13
OT  - LTP
OT  - Medial Prefrontal Cortex
OT  - NMDA Receptor
EDAT- 2015/07/27 06:00
MHDA- 2016/06/15 06:00
PMCR- 2016/11/01
CRDT- 2015/07/27 06:00
PHST- 2015/06/01 00:00 [received]
PHST- 2015/07/14 00:00 [revised]
PHST- 2015/07/15 00:00 [accepted]
PHST- 2015/07/27 06:00 [entrez]
PHST- 2015/07/27 06:00 [pubmed]
PHST- 2016/06/15 06:00 [medline]
PHST- 2016/11/01 00:00 [pmc-release]
AID - S0166-4328(15)30110-8 [pii]
AID - 10.1016/j.bbr.2015.07.039 [doi]
PST - ppublish
SO  - Behav Brain Res. 2015 Nov 1;294:177-85. doi: 10.1016/j.bbr.2015.07.039. Epub 2015 
      Jul 22.