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The role of endocannabinoids in consolidation, retrieval, reconsolidation, and extinction of fear memory

  • Special Issue: Review
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Abstract

Endocannabinoids are involved in various physiological functions, including synaptic plasticity and memory, and some psychiatric disorders, such as posttraumatic stress disorder (PTSD), through the activation of cannabinoid (CB) receptors. Patients with PTSD often show excessive fear memory and impairment of fear extinction (FE). It has been reported that the stability of acquired fear memory is altered through multiple memory stages, such as consolidation and reconsolidation. FE also affects the stability of fear memory. Each stage of fear memory formation and FE are regulated by different molecular mechanisms, including the CB system. However, to the best of our knowledge, no review summarizes the role of the CB system during each stage of fear memory formation and FE. In this review, we summarize the roles of endocannabinoids in fear memory formation and FE. Moreover, based on the summary, we propose a new hypothesis for the role of endocannabinoids in fear regulation, and discuss treatment for PTSD using CB system-related drugs.

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Abbreviations

2-AG:

2-Arachidonoyl glycerol

THC:

Δ9-Tetrahydrocannibinol

AAV:

Adeno-associated virus

AMPA:

α-3-Hydroxy-5-methyl-4-isoxazole propionic acid

ABHD4:

α,β-Hydrolase-4

BLA:

Basolateral amygdale

Camk2:

Ca2+/Calmodulin-dependent protein kinase 2

CREB:

Cyclic AMP response element-binding protein

CB:

Cannabinoid

CBRs:

CB receptors

CB1R:

CB receptor type 1

CB2R:

CB receptor type 2

CeA:

Central nucleus of amygdale

CCK:

Cholecystokinin

CCKB:

CCKB receptor

CS:

Conditioned stimulus

COX-2:

Cyclooxygenase-2

DSI:

Depolarization-induced suppression of inhibition

DSE:

Depolarization-induced suppression of excitation

DAGs:

Diacylglycerols

DAGL:

Diacylglycerol lipases

GDE1:

Glycerophosphodiesterase-1

dlPAG:

Dorsolateral PAG

GPR:

G Protein-coupled receptor

DIO:

Double-floxed inverted open-reading frame

ERK:

Extracellular signal-regulated kinase

FAAH:

Fatty acid amide hydrolase

FC:

Fear conditioning

FE:

Fear extinction

GABA:

γ-Aminobutyric acid

Gad2:

Glutamic acid decarboxylase 2

IL:

Infralimbic cortex

IPN:

Interpeduncular nucleus

I-RTX:

Iodoresiniferatoxin

JNK:

Jun amino terminal kinase

KO:

Knockout

LTD:

Long-term depression

LTP:

Long-term potentiation

mTOR, MAGL:

Mammalian target of rapamycin, Monoacylglycerol lipase

MHb:

Medial habenula

mPFC:

Medial prefrontal cortex

mEPSCs:

Miniature excitatory postsynaptic currents

mIPSCs:

Miniature inhibitory postsynaptic currents

AEA:

N-arachidonoyl ethanolamine

NArPE:

N-arachidonoyl-phosphatidylethanolamines

NAPE-PLD:

N-acyl phosphatidylethanolamine phospholipase D

AA-5HT:

N-arachidonoyl-serotonin

nNOS:

Neuronal nitric oxide synthase

nAChR:

Nicotinic acetylcholine receptor

NMDA:

N-methyl-d-aspartate

PTSD:

Posttraumatic stress disorder

PAG:

Periaqueductal gray

PL:

Prelimbic cortex

RSC:

Retrosplenial cortex

sGC:

Soluble guanylate cyclase

Soluble PLA2:

Soluble phospholipase A2

Trpv1:

Transient receptor potential vanilloid 1

US:

Unconditioned stimulus

WT:

Wild type

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Funding

This research was supported by JSPS KAKENHI Grant Number JP 19K08080.

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S.M. mainly wrote the Sects. 1, 5, 6, and 7. I. M. mainly wrote the Sects. 2, 3, and 4.

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Correspondence to Shingo Matsuda.

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Mizuno, I., Matsuda, S. The role of endocannabinoids in consolidation, retrieval, reconsolidation, and extinction of fear memory. Pharmacol. Rep 73, 984–1003 (2021). https://doi.org/10.1007/s43440-021-00246-y

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