CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice.
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.
Cannich
Astrid
A
Groups of Molecular Genetics of Behavior, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Wotjak
Carsten T
CT
Kamprath
Kornelia
K
Hermann
Heike
H
Lutz
Beat
B
Marsicano
Giovanni
G
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000161:Acoustic Stimulation; D000679:Amygdala / Q000201:enzymology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D019703:Calcineurin / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology*; D003463:Cues; D005108:Extinction, Psychological / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000201:enzymology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D012054:Reinforcement, Psychology; D013997:Time Factors
D011518:Proto-Oncogene Proteins; D043884:Receptor, Cannabinoid, CB1; D011494:Protein Kinases; D019870:1-Phosphatidylinositol 4-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019703:Calcineurin