title: Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
abstract: Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.
authors.affiliation: Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furuyashiki
authors.forename: Shiho
authors.initials: S
authors.lastname: Kitaoka
authors.forename: Yuta
authors.initials: Y
authors.lastname: Senzai
authors.forename: Yuki
authors.initials: Y
authors.lastname: Imoto
authors.forename: Eri
authors.initials: E
authors.lastname: Segi-Nishida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D051545:Cyclooxygenase 1 / Q000172:deficiency; D051546:Cyclooxygenase 2 / Q000172:deficiency; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004291:Dominance-Subordination; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007398:Interpersonal Relations; D018782:Maze Learning; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D001552:Benzazepines; D002135:Calcium-Binding Proteins; D003345:Corticosterone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D004298:Dopamine; D018492:Dopamine Antagonists; D006719:Homovanillic Acid; D008565:Membrane Proteins; D008840:Microfilament Proteins; D016627:Oxidopamine; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; D014446:Tyrosine 3-Monooxygenase; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C491049:Aif1 protein, mouse; C115461:SC 560; C534628:SCH 23390; C496512:Ptgs1 protein, mouse