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

**Tomer Mizrachi Zer-Aviv 1, Larglinda Islami 1, Peter J. Hamilton 2, Eric M. Parise 2, Eric J. Nestler 2, Brenda Sbarski 1 and Irit Akirav 1,\***


**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 shockand 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 sugges<sup>t</sup> 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.

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