Central CRTH2, a second prostaglandin D2 receptor, mediates emotional impairment in the lipopolysaccharide and tumor-induced sickness behavior model

• Published in: The Journal of neuroscience 2014-02, Vol.34 (7), p.2514-2523
• Main Authors: Haba, Ryota, Shintani, Norihito, Onaka, Yusuke, Kanoh, Takuya, Wang, Hyper, Takenaga, Risa, Hayata, Atsuko, Hirai, Hiroyuki, Nagata, Kin-ya, Nakamura, Masataka, Kasai, Atsushi, Hashimoto, Ryota, Nagayasu, Kazuki, Nakazawa, Takanobu, Hashimoto, Hitoshi, Baba, Akemichi
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Disease Models, Animal; Illness Behavior - physiology; Immunohistochemistry; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasms, Experimental - psychology; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Stress, Psychological - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1407-13.2014

Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is a second prostaglandin D2 receptor involved in mediating the allergic response; however, its central function is not yet known. Here, we demonstrate that central CRTH2 mediates emotional impairment. Lipopolysaccharide (LPS)-induced decreases in social interaction and novel exploratory behavior were observed in wild-type (CRTH2(+/+)) mice but not CRTH2-deficient (CRTH2(-/-)) mice, but both genotypes showed hypolocomotion and anorexia following LPS injection. Tumor (colon 26) inoculation, a more pathologically relevant model, induced decreases in social interaction and novel exploratory behavior in CRTH2(+/+), but not CRTH2(-/-) mice. In addition, the CRTH2 antagonists including clinically available ramatroban reversed impaired social interaction and novel exploratory behavior after either LPS or tumor inoculation in CRTH2(+/+) mice. Finally, LPS-induced c-Fos expression in the hypothalamic paraventricular nucleus (PVN) and central amygdala (CeA) was selectively abolished in CRTH2(-/-) mice. These results show that CRTH2 participates in LPS-induced emotional changes and activation in the PVN and CeA. Our study provides the first evidence that central CRTH2 regulates specific emotional behaviors, and that CRTH2 antagonism has potential as a therapeutic target for behavioral symptoms associated with tumors and infectious diseases.