**5. Conclusions**

In many cases, drugs are used in clinical settings without a full understanding of the molecular mechanisms through which they function. Understanding the mechanism of action for a given drug in greater detail has the potential to support further pharmacological development efforts and mitigate the risk of failed clinical trials by stratifying patients to focus on subpopulations most likely to respond to such treatment. We sugges<sup>t</sup> a potentially novel mechanism for the stress-ameliorating effects of URB597 that involves activation of CB1 and the Wnt/β-catenin pathway in the NAc. Overall our findings sugges<sup>t</sup> that FAAH inhibitors may be a viable approach for the treatment of stress-related neuropsychiatric disorders and PTSD in particular and that these therapeutic effects are mediated via a β-catenin-dependent mechanism.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/biomedicines10081789/s1, Figure S1: Antibody specificity; Figure S2: An illustration of a modified herpes simplex virus (HSV) amplicon plasmid; Figure S3: The effects of URB597 on exploration time during the social preference and the social recognition tests; Figure S4: The effects of URB597 and AM251 on exploration time during the social preference and the social recognition tests; Figure S5: The effects of nucleus accumbens (NAc) β-catenin overexpression on exploration time during the social preference and the social recognition tests; Figure S6: The effects of nucleus accumbens (NAc) β-catenin downregulation on exploration time during the social preference and the social recognition tests; Table S1: Pearson bivariate correlation between the expression of β-catenin and behavior.

**Author Contributions:** Conceptualization, I.A. and T.M.Z.-A.; Formal analysis, T.M.Z.-A.; Funding acquisition, I.A.; Investigation, T.M.Z.-A., L.I. and B.S.; Methodology, I.A., T.M.Z.-A., P.J.H., E.M.P. and E.J.N.; Project administration, I.A.; Resources, I.A., P.J.H., E.M.P. and E.J.N.; Supervision, I.A.; Validation, I.A.; Writing—original draft, I.A. and T.M.Z.-A.; Writing—review and editing, I.A. and T.M.Z.-A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Israel Science Foundation (ISF), gran<sup>t</sup> number 993/20 to IA.

**Institutional Review Board Statement:** The animal study protocol was approved by the Institutional Ethics Committee of the University of Haifa (protocol codes 403/2016, 535/2017).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
