Roles and actions of arachidonic acid-derived bioactive lipids in stress-related behaviors

Abstract

Excessive or prolonged stress causes cognitive and emotional changes and is thought to be a risk factor for psychiatric disorders. Recent studies in rodents showed roles and actions of arachidonic acid (AA)-derived bioactive lipids, namely, prostaglandin (PG) E 2 and endocannabinoids (eCB), and their receptors in emotional regulation under psychological stress induced by social and environmental stimuli. Stress exposure increases synthesis of PGE 2 in the brain, which suppresses emotional impulsivity under acute stress and facilitates depression and anxiety-like behaviors under repeated stress. This PGE 2 action is mediated, at least in part, through dopaminergic regulation by EP1, a PGE receptor subtype. Stress exposure also increases synthesis of 2-arachidonoylglycerol (2-AG), one eCB species, which suppresses depression and anxiety-like behaviors through multiple brain structuresthrough its receptor CB1. Thus, stress activates both the PGE 2 -EP1 pathway and the 2-AG-CB1 pathway, which have distinct, mostly opposing, roles in emotional regulation under stress. COX-1, a PGsynthase enriched in microglia, is critical for stress-induced behavioral changes as well as PGE 2 synthesis in the brain. Given a recent report that PGE 2 synthesis in the brain mostly depends on 2-AG metabolism to AA, stress-induced 2-AG synthesis may underlie concomitant PGE 2 synthesis. Collectively, the PGE 2 -EP1 and 2-AG-CB1 pathways as well as their crosstalk may be targets for pharmaceutical development for stress-related pathophysiology in psychiatric disorders.