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

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.

FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats

“…One possible pathway for URB597 regulation of these miRNAs is through Wnt/ β-catenin. We have recently suggested a potentially novel mechanism for the stressameliorating effects of URB597 that involves the activation of CB1r and the Wnt/β-catenin pathway in the nucleus accumbens [39]. Specifically, we suggest that CB1r activation increases PI3K/AKT activity, which phosphorylates GSK-3β via Akt.…”

A Disintegrin and Metalloproteinase 10 (ADAM10) Is Essential for Oligodendrocyte Precursor Development and Myelination in the Mouse Brain

“…4E , F ). Previous results suggested that enhanced anxiety can predispose mice to depression-like behavior under some conditions [ 16 ]. We therefore performed the TST, which is frequently used in studies of depression.…”

“…A series of behavioral analysis showed that ADAM10 cKO mice exhibited the obvious “anxiety and depression-like” performances before they died. Growing evidence has implicated neuroinflammation-induced demyelination as an important pathological feature in major depressive disorder (MDD) and multiple sclerosis (MS), and myelin deficits contribute to mood swing and cognitive decline [ 16 , 17 , 32 ]. Our results using FluoroMyelin Green fluorescent myelin staining, electron microscopy, immunohistochemistry, and western blotting demonstrated that deletion of ADAM10 in OPCs caused significant premyelination on P30 but demyelination on P60.…”

Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats

“…We are aware that translation from our animal model’s results to human depression (and different types of depression) has to be examined carefully. Although FAAH is known to be involved in depression mechanisms in animal studies (the most recent examples [ 82 , 83 ]), much more investigation is needed to ensure the same mechanisms are relevant to humans. However, only a few clinical trials performed till now support the assumption that FAAH plays an important role in depression mechanisms.…”