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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-shock-induced 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 E(2) acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans.

SUBMITTER: Matsuoka Y

PROVIDER: S-EPMC1276058 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Prostaglandin E receptor EP1 controls impulsive behavior under stress.

Matsuoka Yoko Y Furuyashiki Tomoyuki T Yamada Kiyofumi K Nagai Taku T Bito Haruhiko H Tanaka Yasuhiro Y Kitaoka Shiho S Ushikubi Fumitaka F Nabeshima Toshitaka T Narumiya Shuh S

Proceedings of the National Academy of Sciences of the United States of America 20051024 44

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, ...[more]

PMID: 16247016

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Project description:Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.

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Prostaglandin E receptor EP1 controls impulsive behavior under stress.

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Prostaglandin E receptor EP1 controls impulsive behavior under stress.

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