| First Author | Fritz M | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 2 | Pages | 695-705 |
| PubMed ID | 26690700 | Mgi Jnum | J:231184 |
| Mgi Id | MGI:5767050 | Doi | 10.1172/JCI83844 |
| Citation | Fritz M, et al. (2016) Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. J Clin Invest 126(2):695-705 |
| abstractText | Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation. |
