Dual pharmacological inhibitor of endocannabinoid degrading enzymes reduces depressive-like behavior in female rats

Abstract

Major depressive disorder (MDD) is common, often under-treated and a leading cause of disability and mortality worldwide. The causes of MDD remain unclear, including the role of the endocannabinoid system. Intriguingly, the prevalence of depression is significantly greater in women than men. In this study we examined the role of endocannabinoids in depressive behavior. The levels of endocannabinoids, N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured along with brain derived neurotrophic factor (BDNF) in postmortem ventral striata of female patients with MDD and non-psychiatric controls, and in Wistar Kyoto (WKY) rat, a selectively inbred strain of rat widely used for testing the depressive behavior. The effect of pharmacological elevation of endocannabinoids through inhibition of their catabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacyl glycerol lipase [MAGL]) on depressive-like phenotype was also assessed in WKY rat. The findings showed lower levels of endocannabinoids and BDNF in the ventral striatum of MDD patients and WKY rats. A dual inhibitor of FAAH and MAGL, JZL195, elevated the endocannabinods and BDNF levels in ventral striatum, and reduced the depressive-like phenotype in female WKY rats. Collectively, our study

Elevated Brain Fatty Acid Amide Hydrolase Induces Depressive-Like Phenotypes in Rodent Models: A Review

“…The relationship between MAGL and depression has not been as well studied; however, some data suggest that dysregulated 2-AG signaling is implicated in both human and animal studies of depression and that inhibition of MAGL elicits antidepressant-like effects in mice [71][72][73]. A recent investigation used JZL195 to inhibit FAAH and MAGL in female rats to test the effect on depressive behavior [74]. The authors found that JZL195 (3 mg/kg, i.p.)…”

“…Social interaction test. The social interaction test consists of three rooms or chambers: social, neutral and anti-social [74]. A novel rodent is placed into the social chamber before introducing the subject rodent.…”

Endocannabinoid System Components as Potential Biomarkers in Psychiatry

“…Furthermore, a recent study evaluated the effects of JZL195, a dual inhibitor of FAAH and MAGL, in WKY rats. JZL195 elevated the endocannabinoids and BDNF levels in the ventral striatum and reduced the depressive-like phenotype in female WKY rats (202).…”

Exo- and Endo-cannabinoids in Depressive and Suicidal Behaviors

“…For instance, chronic stress significantly downregulates CB1 receptor levels in the hippocampus of male rats, while it upregulates these receptors in the dorsal hippocampus of female rats (90,91). Our recent study revealed a decrease in postmortem levels of AEA and 2-AG in the ventral striatum (nucleus accumbens; NAc) of women with MDD as well as in female Wistar Kyoto (WKY) rat, a genetic model of depression (92). This study also found lower levels of BDNF in the ventral striatum of MDD patients.…”

“…This study also found lower levels of BDNF in the ventral striatum of MDD patients. Interestingly, pharmacological inhibition (by use of JZL195) of the two major endocannabinoid degrading enzymes, FAAH and MAGL, elevated both endocannabinoids and BDNF levels in the ventral striatum, and reduced depressivelike behavior in female rats (92). The ventral striatum has been shown to play a central role in reward and motivation related processes that become dysfunctional in mood disorders (93,94).…”