Prostaglandin E₂ activates the histaminergic system via the EP₄ receptor to induce wakefulness in rats

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.