RRC ID 16147
Author Tanaka K, Furuyashiki T, Kitaoka S, Senzai Y, Imoto Y, Segi-Nishida E, Deguchi Y, Breyer RM, Breyer MD, Narumiya S.
Title Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
Journal J Neurosci
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.
Volume 32(12)
Pages 4319-29
Published 2012-3-21
DOI 10.1523/JNEUROSCI.5952-11.2012
PII 32/12/4319
PMID 22442093
PMC PMC3784244
MeSH 3,4-Dihydroxyphenylacetic Acid / metabolism Analysis of Variance Animals Benzazepines / pharmacology Calcium-Binding Proteins / metabolism Corticosterone / blood Cyclooxygenase 1 / deficiency Cyclooxygenase 2 / deficiency Cyclooxygenase Inhibitors Dinoprostone / genetics Dinoprostone / metabolism* Disease Models, Animal Disease Susceptibility Dominance-Subordination* Dopamine / metabolism* Dopamine Antagonists / pharmacology Homovanillic Acid / metabolism Interpersonal Relations Maze Learning Membrane Proteins / deficiency Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Microfilament Proteins / metabolism Neural Pathways / drug effects Neural Pathways / metabolism Oxidopamine / toxicity Prefrontal Cortex / drug effects Prefrontal Cortex / injuries Prefrontal Cortex / metabolism* Pyrazoles / pharmacology Receptors, Prostaglandin E / deficiency Signal Transduction / drug effects Signal Transduction / physiology* Stress, Psychological* / metabolism Stress, Psychological* / pathology Stress, Psychological* / prevention & control Sulfonamides / pharmacology Time Factors Tyrosine 3-Monooxygenase / metabolism Ventral Tegmental Area / drug effects Ventral Tegmental Area / metabolism*
IF 5.674
Times Cited 67
Mice RBRC02412