Inhibition of fatty acid binding protein 5 prevents stress-induced anxiogenic and depressive-like symptoms through modulation of hippocampal neurogenesis, cannabinoid and neurotrophic signaling in the limbic circuitry

The endocannabinoid (eCB) system modulates many biological processes, including adult neurogenesis, emotional behaviour and stress-related signaling pathways. Intrinsic levels of eCB ligands, such as anandamide, are regulated in part, by fatty acid binding protein 5 (FABP5), a chaperone protein that transports anandamide for hydrolysis. Here, using preclinical rodent models, we examined the effects of pharmacological FABP5 inhibition on anxiety- and depressive-like behaviours and associated molecular signaling pathways, following exposure to chronic stress. In addition, we investigated the impacts of chronic stress on hippocampal neurogenesis and how FABP5 inhibition may modulate stress-induced deficits in hippocampal neurogenic mechanisms. Remarkably, we report that anxiety- and depressive-like behaviours are strongly prevented by systemic FABP5 inhibition and associated with altered transcription of IGF-1, CB₂ and GPR₅₅ receptors as well as by altered phosphorylation of Erk1/2, Akt and p70S6 kinase pathways in the limbic circuitry. Finally, FABP5 inhibition potently blocked stress-induced reductions in hippocampal neurogenesis, identifying FABP5 inhibition as a promising pharmacotherapeutic candidate for stress-induced mood and anxiety symptoms.