Journal Article

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

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

2022

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Anandamide / Antidepressants / Anxiety / Behavior / Cannabinoid CB1 receptors / Cannabinoids / CB1 receptor / Fatty-acid amide hydrolase / Freezing / Gene expression / Gene transfer / Glutamic acid receptors (metabotropic) / Health aspects / Hedonic response / Hydrolase / Immunological memory / Kinases / Memory / Mental depression / Mental disorders / mGluR5 / Nucleus accumbens / Post traumatic stress disorder / post-traumatic stress disorder (PTSD) / Prefrontal cortex / rat / Social behavior / Social interactions / Startle response / URB597 / β-Catenin