The role of prefrontal cortex CB1 receptors in the modulation of fear memory
Abstract
Understanding the mechanism of how fear memory can be extinguished could provide potential therapeutic strategies for the treatment of posttraumatic stress disorders. Here we show that infusion of CB1 receptor antagonist into the infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) retarded cue-alone-induced reduction of fear-potentiated startle. Conversely, cannabinoid agonist WIN55212-2 (WIN) facilitated the extinction. Unexpectedly, administration of WIN without cue-alone trials reduced startle potentiation in a dose-dependent manner. The effect of cannabinoid agonists was mimicked by endocannabinoid uptake or fatty acid amide hydrolase inhibitors. Rats were trained with 10 conditioned stimulus (CS(+)) (yellow light)-shock pairings. Extinction training with CS(+) (yellow light)-alone but not CS(-) (blue light)-alone trials decreased fear-potentiated startle. Intra-IL infusion of WIN before CS(-)-alone trials decreased startle potentiation, suggesting that the cannabinoid agonist decreased conditioned fear irrespective of whether the rats underwent CS(+)- or CS(-)-alone trials. Cannabinoid agonists activated extracellular signal-regulated kinases (ERKs) in mPFC slices, and ERK inhibitor blocked the effect of cannabinoid agonists on fear-potentiated startle. These results suggest that CB1 receptors acting through the phosphorylation of ERK are involved not only in the extinction of conditioned fear but also in the adaptation to aversive situations in general.
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Activating CB1R via systemic or intra-hippocampal or intra-mPFC administration of WIN55212-2, AM404, or AEA facilitates rodent fear extinction, in most cases without affecting conditioned fear.
“Activating CB1R via systemic or intra-hippocampal or -mPFC administration of either the CB1R agonist, WIN55212-2, the ECB reuptake blocker, AM404, or AEA itself has been shown to facilitate rodent fear extinction, in most cases without affecting conditioned fear [89,95–98] (but see [90]).”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [90]
Infusing SR141716A directly into the BLA or mPFC is sufficient to impair cued fear extinction in rats.
“Subsequent studies showed that infusing SR141716A directly into the BLA (or mPFC [90]) was sufficient to impair a cued fear extinction in rats [91,92].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [90]
Rats infused with the FAAH inhibitor URB597 into the mPFC prior to extinction training show improved extinction retrieval when subsequently tested drug-free.
“Rats infused with the FAAH inhibitor, URB597, into the mPFC prior to extinction training show improved extinction retrieval when subsequently tested drug-free [90].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [90]
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- Authors
- Lin, H.-C., Mao, S.-C., Su, C.-L., & Gean, P.-W.
- Affiliations
- National Cheng Kung University (TW)
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-05-13
- Volume
- 19
- Issue
- 1
- Pages
- 165-175
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- OpenAlex
- W2153865976
- Cited by
- 119
- References
- 52
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 10 · 2016: 10 · 2015: 11 · 2014: 13 · 2013: 5 · 2012: 9
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council (NSC94-2752-B-006-001-PAE)
- 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, fear potentiation, infralimbic cortex, medial prefrontal cortex, cannabinoid receptor agonists, WIN 55,212-2, endocannabinoids, fatty acid amide hydrolase, ERK1/2 phosphorylation, fear conditioning, post-traumatic stress disorder, startle potentiation
- MeSH terms
- Adaptation, Physiological, Adaptation, Psychological, Animals, Extinction, Psychological, Fear, Male, Memory, Rats, Sprague-Dawley, Prefrontal Cortex, Receptor, Cannabinoid, CB1, Rats
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