Recent studies have suggested that activation of hippocampal AMPK ameliorates cognitive functions in both rodents and patients. However, roles of AMPK on emotional function are unclear. Thus, we examined the effects of 5-aminoimidazole-4-carboxamide riboside (AICAR), an AMPK activator, on depressive-like behavior in olfactory bulbectomized (OBX) mice, an animal model of depression.
Mice were injected with AICAR for 1-14 days and then subjected tail-suspension test on the 21st day after surgery. Hippocampal proteins were assessed by western blotting, and neurogenesis was measured by immunohistochemical method.
Subchronic treatment with AICAR decreased immobility time in OBX mice. Phosphorylated AMPK, protein kinase C (PKC) ζ, nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB) and the protein level of brain derived neurothrophic factor (BDNF) in OBX mice were increased by AICAR. AICAR reversed hippocampal neurogenesis in OBX. Anti-depressant effect of AICAR in TST was attenuated by co-administration of ZIP, a PKCζ inhibitor.
Our data suggested that AMPK activation induced antidepressant effect through PKCζ/NF-κB/BDNF/CREB pathways. Therefore, AMPK may become a new therapeutic target of depression.

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