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) E2 and endocannabinoids (eCB), and their receptors in emotional regulation under psychological stress induced by social and environmental stimuli. Stress exposure increases synthesis of PGE2 in the brain, which suppresses emotional impulsivity under acute stress and facilitates depression and anxiety-like behaviors under repeated stress. This PGE2 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 structures through its receptor CB1. Thus, stress activates both the PGE2-EP1 pathway and the 2-AG-CB1 pathway, which have distinct, mostly opposing, roles in emotional regulation under stress. COX-1, a PG synthase enriched in microglia, is critical for stress-induced behavioral changes as well as PGE2 synthesis in the brain. Given a recent report that PGE2 synthesis in the brain mostly depends on 2-AG metabolism to AA, stress-induced 2-AG synthesis may underlie concomitant PGE2 synthesis. Collectively, the PGE2-EP1 and 2-AG-CB1 pathways as well as their crosstalk may be targets for pharmaceutical development for stress-related pathophysiology in psychiatric disorders.