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

Ryota Haba; Norihito Shintani; Yusuke Onaka; Takuya Kanoh; Hyper Wang; Risa Takenaga; Atsuko Hayata; Hiroyuki Hirai; Kin-ya Nagata; Masataka Nakamura; Atsushi Kasai; Ryota Hashimoto; Kazuki Nagayasu; Takanobu Nakazawa; Hitoshi Hashimoto; Akemichi Baba

doi:10.1523/JNEUROSCI.1407-13.2014

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

J Neurosci. 2014 Feb 12;34(7):2514-23. doi: 10.1523/JNEUROSCI.1407-13.2014.

Authors

Ryota Haba¹, Norihito Shintani, Yusuke Onaka, Takuya Kanoh, Hyper Wang, Risa Takenaga, Atsuko Hayata, Hiroyuki Hirai, Kin-ya Nagata, Masataka Nakamura, Atsushi Kasai, Ryota Hashimoto, Kazuki Nagayasu, Takanobu Nakazawa, Hitoshi Hashimoto, Akemichi Baba

Affiliation

¹ Laboratory of Molecular Neuropharmacology and Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Suita, Osaka 565-0871, Japan, Department of Advanced Medicine and Development, Bio Medical Laboratories, Kawagoe, Saitama 350-1101, Japan, Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Department of Psychiatry, Graduate School of Medicine, and iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan, and Faculty of Pharmaceutical Sciences, Hyogo University of Health Science, Kobe, Hyogo 650-8530, Japan.

Abstract

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.

Keywords: c-Fos; cyclooxygenase; lipopolysaccharide; prostaglandin D2 receptor; social interaction; tumor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*

Substances

Lipopolysaccharides
Receptors, Immunologic
Receptors, Prostaglandin
prostaglandin D2 receptor