Prostaglandin E receptor EP1 controls impulsive behavior under stress

Abstract

Animals under stress take adaptive actions that may lead to various types of behavioral disinhibition. Such behavioral disinhibition, when expressed excessively and impulsively, can result in harm in individuals and cause a problem in our society. We now show that, under social or environmental stress, mice deficient in prostaglandin E receptor subtype EP1 (Ptger1 ؊/؊ ) manifest behavioral disinhibition, including impulsive aggression with defective social interaction, impaired cliff avoidance, and an exaggerated acoustic startle response. This phenotype was reproduced in wild-type mice by administration of an EP1-selective antagonist, whereas administration of an EP1-selective agonist suppressed electric-shockinduced impulsive aggression. Dopamine turnover in the frontal cortex and striatum was increased in Ptger1 ؊/؊ mice, and administration of dopaminergic antagonists corrected their behavioral phenotype. These results suggest that prostaglandin E2 acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans.dopamine ͉ aggression ͉ behavioral disinhibition A ll organisms are repeatedly disturbed or threatened by changes in the internal or external environment. Such a state of perturbed homeostasis is referred to as ''stress'' (1, 2). Stress results not only from physical stimuli, such as heat, injury, or disease but also from psychological stimuli, such as exposure to a novel environment or a predator. Stress manifests itself in various characteristic responses that include emotions such as fear and aggression and activation of the neuroendocrine and sympathetic nervous systems (3). These stress responses are thought to be initiated and regulated in the CNS by biochemical processes that are evoked by threatening stimuli (''stressors'') and that determine the activity of several distinct but interacting neuronal pathways (4). However, the neural mechanisms responsible for initiation and regulation of stress responses have remained largely unknown. Neither is it known whether different forms of stressors (for example, physical vs. psychological stimuli) mobilize the same or distinct mechanisms to initiate and regulate their stress responses. Given that the stress responses are elicited to promote adaptation, severe dysfunction of either initiation or regulation mechanisms can not only be a threat to survival, but can also result in various physiological, psychological, or even psychiatric disorders (3, 5).We have been studying the roles of prostaglandins (PGs) in various physiological and pathophysiological processes. PGs are arachidonic acid metabolites formed by the sequential actions of cyclooxygenase (COX) and respective synthases, and they include PGD 2 , PGE 2 , PGF 2␣ , PGI 2 , and thromboxane A 2 . PGs interact with eight types or subtypes of G protein-coupled receptors, including the PGD receptor, four subtypes of PGE receptor (EP1, EP2, EP3, and EP4, which are encoded respectively by the genes Ptger1...

Central PGE2exhibits anxiolytic-like activity via EP1and EP4receptors in a manner dependent on serotonin 5-HT1A, dopamine D1and GABAAreceptors

“…This action of PGE 2 was abolished in mice treated with an EP 4 PGE 2 is a bioactive lipid produced from arachidonic acid, via PGH 2 , by cyclooxygenase (COX), and acts on its receptors close to its synthesis [6]. Under normal physiological conditions, brain-cell population expressing either COX isoform constitutively, namely, glial COX-1 and neuronal COX-2, might contribute to PGE 2 production [11,26]. Further investigation will elucidate how PGE 2 is released in response to various stresses including psychological stress not related to sickness.…”

“…Pro-inflammatory cytokines released by activation of the innate immune system are known to induce expression of COX-2 and microsomal PGE synthase (mPGES)-1 in the brain microvessels, and PGE 2 might be released and distributed to the large brain area [11]. In the PVN, an important site in the HPA axis, expression of COX-2 and EP 4 is particularly induced by LPS administration [9,27].…”

“…Both EP 1 and EP 3 receptor work critically in activation of the hypothalamic-pituitary-adrenal (HPA) axis after LPS administration [9]. Interestingly, psychological stress not related sickness also enhances PG production in the CNS [10,11]; however, the mechanism underlying the emotional regulation of central PGs is largely unknown. We have recently reported that PGD 2 , a structural isomer of PGE 2 , has anxiolytic-like activity via DP 1 receptor among two receptor subtypes for PGD 2 [12].…”

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

“…Ptger1-null mice show behavioral inhibition, manifested as impulsive aggression with defective social interaction, impaired cliff avoidance and an exaggerated acoustic startle response when under social or environmental stress. 20 Haploinsufficiency of this gene might be responsible for the severe behavioral traits in case 1 and the hyperactivity in cases 2 and 3.…”

Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice

“…The rotating rod test, the hanging test, and the cliff avoidance test were performed as previously described (Shimizu et al, 2002;Matsuoka et al, 2005). The rotating rod test and the hanging test were performed when offspring male mice were five weeks old.…”