Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.

Tanaka K, Furuyashiki T, Kitaoka S, Senzai Y, Imoto Y, Segi-Nishida E, Deguchi Y, Breyer RM, Breyer MD, Narumiya S
J Neurosci. 2012 32 (12): 4319-29

PMID: 22442093 · PMCID: PMC3784244 · DOI:10.1523/JNEUROSCI.5952-11.2012

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.

MeSH Terms (35)

3,4-Dihydroxyphenylacetic Acid Analysis of Variance Animals Benzazepines Calcium-Binding Proteins Corticosterone Cyclooxygenase 1 Cyclooxygenase 2 Cyclooxygenase Inhibitors Dinoprostone Disease Models, Animal Disease Susceptibility Dominance-Subordination Dopamine Dopamine Antagonists Homovanillic Acid Interpersonal Relations Maze Learning Membrane Proteins Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Microfilament Proteins Neural Pathways Oxidopamine Prefrontal Cortex Pyrazoles Receptors, Prostaglandin E Signal Transduction Stress, Psychological Sulfonamides Time Factors Tyrosine 3-Monooxygenase Ventral Tegmental Area

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