Enhancing Endocannabinoid Signaling via β-Catenin in the Nucleus Accumbens Attenuates PTSD- and Depression-like Behavior of Male Rats

Tomer Mizrachi Zer-Aviv, Larglinda Islami, Peter J. Hamilton, Eric M. Parise, Eric J. Nestler, Brenda Sbarski, Irit Akirav

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibition of fatty acid amide hydrolase (FAAH), which increases anandamide levels, has been suggested as a potential treatment for stress-related conditions. We examined whether the stress-preventing effects of the FAAH inhibitor URB597 on behavior are mediated via β-catenin in the nucleus accumbens (NAc). Male rats were exposed to the shock and reminders model of PTSD and then treated with URB597 (0.4 mg/kg; i.p.). They were tested for anxiety- (freezing, startle response), depression-like behaviors (despair, social preference, anhedonia), and memory function (T-maze, social recognition). We also tested the involvement of the CB1 receptor (CB1r), β-catenin, and metabotropic glutamate receptor subtype 5 (mGluR5) proteins. URB597 prevented the shock- and reminders-induced increase in anxiety- and depressive-like behaviors, as well as the impaired memory via the CB1r-dependent mechanism. In the NAc, viral-mediated β-catenin overexpression restored the behavior of rats exposed to stress and normalized the alterations in protein levels in the NAc and the prefrontal cortex. Importantly, when NAc β-catenin levels were downregulated by viral-mediated gene transfer, the therapeutic-like effects of URB597 were blocked. We suggest a potentially novel mechanism for the therapeutic-like effects of FAAH inhibition that is dependent on β-catenin activation in the NAc in a PTSD rat model.

Original languageEnglish
Article number1789
JournalBiomedicines
Volume10
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
This research was funded by the Israel Science Foundation (ISF), grant number 993/20 to IA.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • cannabinoids
  • CB1 receptor
  • fatty acid amide hydrolase (FAAH)
  • mGluR5
  • post-traumatic stress disorder (PTSD)
  • rat
  • URB597
  • β-catenin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology (all)

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