Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to early life stress

Early life stress (ELS) may increase predisposition to depression. Despite extensive research, there is still a lack of knowledge of how to optimally treat depression. We aimed to establish a role for the endocannabinoid (ECB) system within the hippocampal-nucleus accumbens (NAc) network as a possible effective target in combating the pathophysiological development of depression-like behavior and neuronal alterations that are precipitated by ELS. Male and female rats were exposed to ELS during post-natal days (P) 7–14, injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184 for 2 weeks during late-adolescence (P45–60). Rats were tested starting at P90 for depressive- and anxiety-like behaviors as well as social preference and recognition; alterations in FAAH and MAGL activity; the expression of brain-derived neurotrophic factor (BDNF); and plasticity in the hippocampal-NAc pathway. FAAH and MAGL inhibitors during late-adolescence prevented: (i) the long-term effects of ELS on depression- and anxiety-like behavior and the impairment in social behavior and neuronal plasticity in males and females; (ii) ELS-induced alterations in MAGL activity in males' hippocampus and females' hippocampus and NAc; and (iii) ELS-induced alterations in BDNF in males' hippocampus and NAc and females' hippocampus. Significant correlations were observed between alterations in MAGL and BDNF levels and the behavioral phenotype. The findings suggest that alterations in MAGL activity and BDNF expression in the hippocampal-NAc network contribute to the depressive-like behavioral phenotype in ELS males and females. Moreover, the study suggests FAAH and MAGL inhibitors as potential intervention drugs for depression.