The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear

Hippocampus. 2003;13(1):53-8. doi: 10.1002/hipo.10043.


Pavlovian conditioning involves the association of initially neutral conditioned stimuli (CS) with unconditioned stimuli (US) that elicit a response. In contextual fear conditioning in rodents, the CS is the context of a training apparatus and the US is a foot shock. Retrieval of memory of the training is tested by presenting the CS alone. But a retrieval test also initiates extinction of the conditioned response. That is, presentation of the CS alone results in new learning, i.e., the CS no longer predicts the US. Here we report that extinction is triggered by two hippocampal signaling pathways underlying retrieval (the cAMP-dependent protein kinase and the mitogen-activated protein kinase pathways) and two other mechanisms that become activated at the same time and are not necessary for retrieval (N-methyl-D-aspartate glutamatergic receptors and the calcium/calmodulin-dependent protein kinase II signaling pathway). Thus, the molecular mechanisms underlying acquisition and/or consolidation of the memory for extinction are similar to those described for the acquisition and/or consolidation of the original contextual fear.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Fear / drug effects
  • Fear / physiology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Learning / drug effects
  • Learning / physiology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Male
  • Memory / drug effects
  • Memory / physiology
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases