Faculty Collaboration Database

Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity. Neuropsychopharmacology 2018 Sep;43(10):2017-2027

Date

07/07/2018

Pubmed ID

29977073

Pubmed Central ID

PMC6098035

DOI

10.1038/s41386-018-0135-4

Scopus ID

2-s2.0-85049559833 (requires institutional sign-in at Scopus site)   55 Citations

Abstract

Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

Author List

Segev A, Korem N, Mizrachi Zer-Aviv T, Abush H, Lange R, Sauber G, Hillard CJ, Akirav I

Author

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amidohydrolases
Amygdala
Animals
Benzamides
CA1 Region, Hippocampal
Carbamates
Electroshock
Emotions
Endocannabinoids
Extinction, Psychological
Fear
Hippocampus
Long-Term Potentiation
Male
Memory
Microinjections
Neuronal Plasticity
Rats
Rats, Sprague-Dawley