CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice

Learn Mem. 2004 Sep-Oct;11(5):625-32. doi: 10.1101/lm.77904.


Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Acoustic Stimulation
  • Amygdala / enzymology
  • Animals
  • Blotting, Western
  • Brain / enzymology*
  • Calcineurin / metabolism*
  • Conditioning, Classical / physiology*
  • Cues
  • Extinction, Psychological / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fear / physiology*
  • Hippocampus / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prefrontal Cortex / enzymology
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Reinforcement, Psychology
  • Time Factors


  • Proto-Oncogene Proteins
  • Receptor, Cannabinoid, CB1
  • Protein Kinases
  • 1-Phosphatidylinositol 4-Kinase
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Calcineurin