Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
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Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA (received for review June 13, 2005)
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 E2 acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans.
Footnotes
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↵ †† To whom correspondence should be addressed. E-mail: snaru{at}mfour.med.kyoto-u.ac.jp.
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↵ ‡ Y.M. and T.F. contributed equally to this work.
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↵ ¶ Present address: Laboratory of Neuropsychopharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan.
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↵ ∥ Present address: Department of Neurochemistry, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan.
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↵ ** Present address: Department of Pharmacology, Asahikawa Medical College, Asahikawa 078-8510, Japan.
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Author contributions: Y.M., T.F., K.Y., T. Nagai, H.B., F.U., T. Nabeshima, and S.N. designed research; Y.M., T.F., K.Y., T. Nagai, H.B., Y.T., and S.K. performed research; Y.M., T.F., K.Y., T. Nagai, H.B., Y.T., S.K., T. Nabeshima, and S.N. analyzed data; and Y.M., T.F., H.B., and S.N. wrote the paper.
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Conflict of interest statement: Our work has been partially supported by Ono Pharmaceuticals, and Ono Pharmaceuticals has applied for a patent on our findings of potential use of EP1-agonists as therapeutic agents for post-traumatic stress disorder.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: ACTH, adrenocorticotropic hormone; COX, cyclooxygenase; DA, dopamine; HPA, hypothalamo–pituitary–adrenal; i.c.v., intracerebroventricularly; PG, prostaglandin.
- Copyright © 2005, The National Academy of Sciences
Prostaglandin E receptor EP1 controls impulsive behavior under stress
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