Augmentation of fear extinction by D-cycloserine is blocked by proteasome inhibitors

Neuropsychopharmacology. 2008 Dec;33(13):3085-95. doi: 10.1038/npp.2008.30. Epub 2008 Mar 26.


D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fear-potentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amygdala / drug effects*
  • Amygdala / metabolism
  • Animals
  • Antimetabolites / pharmacology
  • Cycloserine / pharmacology*
  • Disks Large Homolog 4 Protein
  • Electric Stimulation
  • Endocytosis / drug effects
  • Endocytosis / physiology
  • Enzyme Inhibitors / pharmacology*
  • Excitatory Amino Acid Agonists / pharmacology
  • Extinction, Psychological / drug effects*
  • Extinction, Psychological / physiology
  • Fear / drug effects*
  • Fear / physiology
  • Intracellular Signaling Peptides and Proteins / drug effects
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / drug effects
  • Membrane Proteins / metabolism
  • Organ Culture Techniques
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / drug effects*
  • Receptors, AMPA / metabolism
  • Reflex, Startle / drug effects
  • Reflex, Startle / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Adaptor Proteins, Signal Transducing
  • Antimetabolites
  • Disks Large Homolog 4 Protein
  • Dlg1 protein, rat
  • Dlg4 protein, rat
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proteasome Inhibitors
  • Receptors, AMPA
  • Cycloserine
  • Proteasome Endopeptidase Complex
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1