PT - JOURNAL ARTICLE AU - Kohei Tanaka AU - Tomoyuki Furuyashiki AU - Shiho Kitaoka AU - Yuta Senzai AU - Yuki Imoto AU - Eri Segi-Nishida AU - Yuichi Deguchi AU - Richard M. Breyer AU - Matthew D. Breyer AU - Shuh Narumiya TI - Prostaglandin E<sub>2</sub>-Mediated Attenuation of Mesocortical Dopaminergic Pathway Is Critical for Susceptibility to Repeated Social Defeat Stress in Mice AID - 10.1523/JNEUROSCI.5952-11.2012 DP - 2012 Mar 21 TA - The Journal of Neuroscience PG - 4319--4329 VI - 32 IP - 12 4099 - http://www.jneurosci.org/content/32/12/4319.short 4100 - http://www.jneurosci.org/content/32/12/4319.full SO - J. Neurosci.2012 Mar 21; 32 AB - 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 E2 (PGE2), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE2 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 PGE2-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.