PMID- 20935233
OWN - NLM
STAT- MEDLINE
DCOM- 20110118
LR  - 20211020
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 336
IP  - 1
DP  - 2011 Jan
TI  - Down-regulation of synaptic GluN2B subunit-containing N-methyl-D-aspartate 
      receptors: a physiological brake on CA1 neuron 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hyperexcitability during 
      benzodiazepine withdrawal.
PG  - 265-73
LID - 10.1124/jpet.110.174235 [doi]
AB  - A significant link was previously established between benzodiazepine withdrawal 
      anxiety and a progressive increase in 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 
      potentiation in hippocampal CA1 neurons from rats withdrawn up to 2 days from 
      1-week oral administration of the benzodiazepine flurazepam (FZP). Despite AMPAR 
      current potentiation, withdrawal anxiety was masked by a 2-fold reduction in CA1 
      neuron N-methyl-D-aspartate receptor (NMDAR) currents since preinjection of an 
      NMDA antagonist restored NMDAR currents and unmasked anxiety in 2-day 
      FZP-withdrawn rats. In the current study, GluN subunit levels in postsynaptic 
      density (PSD)-enriched subfractions of CA1 minislices were compared with 
      GluN2B-mediated whole-cell currents evoked in CA1 neurons in hippocampal slices 
      from 1- and 2-day FZP-withdrawn rats. GluN1 and GluN2B, although not the 
      phosphoSer1303-GluN2B ratio or GluN2A subunit levels, were decreased in PSD 
      subfractions from 2-day, but not 1-day, FZP-withdrawn rats. Consistent with 
      immunoblot analyses, GluN2B-mediated NMDAR currents evoked in slices from 2-day 
      FZP-withdrawn rats were decreased in the absence, but not the presence, of the 
      GluN2B subunit-selective antagonist ifenprodil. In contrast, ifenprodil-sensitive 
      NMDAR currents were unchanged in slices from 1-day withdrawn rats. Because AMPA 
      (1 muM) preincubation of slices from 1-day FZP-withdrawn rats induced depression 
      of GluN2B subunit-mediated currents, depression of NMDAR currents was probably 
      secondary to AMPAR potentiation. CA1 neuron NMDAR currents were depressed  approximately 50% 
      after 2-day withdrawal and offset potentiation of AMPAR-mediated currents, 
      leaving total charge transfer unchanged between groups. Collectively, these 
      findings suggest that a reduction of GluN2B-containing NMDAR may serve as a 
      homeostatic feedback mechanism to modulate glutamatergic synaptic strength during 
      FZP withdrawal to alleviate benzodiazepine withdrawal symptoms.
FAU - Shen, Guofu
AU  - Shen G
AD  - Department of Physiology and Pharmacology, University of Toledo College of 
      Medicine, Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA.
FAU - Tietz, Elizabeth I
AU  - Tietz EI
LA  - eng
GR  - R01 DA018342/DA/NIDA NIH HHS/United States
GR  - R01-DA018342/DA/NIDA NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20101008
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
SB  - IM
MH  - Animals
MH  - Benzodiazepines/*toxicity
MH  - CA1 Region, Hippocampal/drug effects/*physiology
MH  - Down-Regulation/drug effects/physiology
MH  - Male
MH  - Neurons/drug effects/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Substance Withdrawal Syndrome/*metabolism
MH  - Synapses/drug effects/*metabolism
MH  - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*pharmacology
PMC - PMC3014299
EDAT- 2010/10/12 06:00
MHDA- 2011/01/19 06:00
PMCR- 2012/01/01
CRDT- 2010/10/12 06:00
PHST- 2010/10/12 06:00 [entrez]
PHST- 2010/10/12 06:00 [pubmed]
PHST- 2011/01/19 06:00 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - jpet.110.174235 [pii]
AID - 3651339 [pii]
AID - 10.1124/jpet.110.174235 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2011 Jan;336(1):265-73. doi: 10.1124/jpet.110.174235. Epub 
      2010 Oct 8.