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The Journal of Neuroscience, July 9, 2003, 23(14):5975-5983

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Prostaglandin E₂ Activates the Histaminergic System via the EP₄ Receptor to Induce Wakefulness in Rats

Zhi-Li Huang,¹ Yo Sato,¹ Takatoshi Mochizuki,¹ Tetsuya Okada,^1,3 Wei-Min Qu,¹ Atsushi Yamatodani,⁴ Yoshihiro Urade,^1,2 and Osamu Hayaishi¹

¹Department of Molecular Behavioral Biology, Osaka Bioscience Institute, and ²Core Research for Evolutional Science and Technology, Japan Science Technology Corporation, Osaka 565-0874, Japan, ³Department of Medical Science III, School of Health and Sport Sciences, Osaka University, Osaka 560-0043, Japan, and ⁴Department of Medical Physics, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan

Prostaglandin (PG)E₂ promotes the wakeful state when administered into the posterior hypothalamus, in which the histaminergic tuberomammillary nucleus (TMN) is located. To explore the neurotransmitter mechanisms responsible for PGE₂-induced wakefulness in rats, we examined the effect of PGE₂ on the activity of the histaminergic system and the involvement of PGE₂ receptor subtypes in the response. PGE₂ perfusion in the TMN at doses of 100, 200, and 400 pmol/min for 2 hr significantly increased histamine release from the medial preoptic area and frontal cortex in a dose-dependent manner, as measured by in vivo microdialysis. Among the agonists of the four distinct subtypes of PGE₂ receptors (EP_1–4) tested, only the EP₄ receptor agonist (ONO-AE1-329) mimicked the excitatory effect of PGE₂ on histamine release from both the medial preoptic area and frontal cortex. Perfusion of either PGE₂ or the EP₄ agonist into the TMN at a dose of 200 pmol/min for 1 hr increased histidine decarboxylase activity, histidine decarboxylase mRNA level, and histamine content in the hypothalamus. In situ hybridization revealed that EP₄ receptor mRNA was expressed in histidine decarboxylase-immunoreactive neurons of the TMN region. Furthermore, EP₄ agonist perfusion into the TMN induced wakefulness. These findings indicate that PGE₂ induces wakefulness through activation of the histaminergic system via EP₄ receptors.

Key words: prostaglandin E₂; EP receptors; histamine; histidine decarboxylase; wakefulness; microdialysis; rat

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Received Jan. 3, 2003; revised Apr. 24, 2003; accepted May. 7, 2003.

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