CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice
Open accessAbstract
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.
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CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels and positively regulates inwardly rectifying K+ channels, as well as calcineurin, to change the phosphorylation state of effector molecules.
“In addition, CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels [26] and positively regulates inwardly rectifying K+ channels [26,27], as well as protein serine/threonine phosphatase 2B (calcineurin, PP2B) to change the phosphorylation state of various effector molecules [28,29].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [28]
CB1R knockout or systemic antagonist (SR141716A) administration produces impairments in extinction learning but not fear conditioning.
“and produced impairments in extinction learning (but not fear conditioning) by CB1R KO or systemic antagonist (SR141716A) administration [28,86]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [28]
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- Authors
- Cannich, A., Wotjak, C. T., Kamprath, K., Hermann, H., Lutz, B., & Marsicano, G.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Venue
- Learning & Memory
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-09
- Volume
- 11
- Issue
- 5
- Pages
- 625-632
- ISSN
- 1072-0502 (ISSN-L)
- 1549-5485
- PMC
- PMC523082
- OpenAlex
- W2144069251
- Cited by
- 130
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 10 · 2012: 5
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Learning & Memory (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CB1 receptor, fear extinction, conditioned fear memory, ERK1/2 phosphorylation, Akt phosphorylation, calcineurin, endocannabinoid system, basolateral amygdala, central amygdala, ventromedial prefrontal cortex, dorsal hippocampus, ventral hippocampus, aversive memory
- MeSH terms
- Acoustic Stimulation, Amygdala, Animals, Brain, Conditioning, Classical, Cues, Extinction, Psychological, Fear, Hippocampus, Male, Mice, Inbred C57BL, Protein Kinases, Proto-Oncogene Proteins, Reinforcement, Psychology, Time Factors, Blotting, Western, Protein Serine-Threonine Kinases, Prefrontal Cortex, Mice, Knockout, Calcineurin, 1-Phosphatidylinositol 4-Kinase, Receptor, Cannabinoid, CB1, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Mice
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