Cortical miR-16 involvement in the antidepressant effects of pharmacological elevation of anandamide in a rat model for depression

Introduction: Early life stress (ELS) significantly increases predisposition to depression. Here, we examined whether the restoring effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, which elevates anandamide levels, are associated with alterations in microRNAs (miRNAs) related with depression and whether specific miRNAs have a crucial role in the antidepressant-like effect of URB597. Methods: In experiment 1, male rats were exposed to ELS using the "Limited Bedding and Nesting" paradigm from postnatal day (P)7 to P14. During P45 to P60 (late-adolescence), URB597 (0.4 mg/kg) or vehicle were administered i.p. for 2 weeks. On P90 (adulthood), rats were tested for depressive-like behavior (i.e., social memory and learned helplessness), and the expression of miR-16 in the medial prefrontal cortex (mPFC) was measured. In experiment 2, ELS-exposed rats were injected with antagomiR-16 or saline into the right ventricle on P38, before the chronic treatment with URB597 and tested for social memory and learned helplessness on P90. Results: URB597 restored the ELS-induced depressive phenotype and normalized the downregulation in mPFC-miR-16. Importantly, after downregulating mPFC-miR-16 using the antagomir, the therapeutic-like effects of URB597 were significantly blunted. Conclusions: Our findings show for the first time that enhancing anandamide signaling can prevent an ELS-induced decrease in a specific miR in the mPFC and the associated depressive-like phenotype. Moreover, miR-16 in the mPFC plays a crucial role in the antidepressant-like effects of URB597. The findings suggest a novel mechanism involving miRNAs in anandamide`s therapeutic effects.