Journal Article

DKFZ-2017-01975

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice.

Fritz, M. ; Klawonn, A. M. ; Nilsson, A. ; Singh, A. K. ; Zajdel, J. ; Wilhelms, D. B. ; Lazarus, M. ; Löfberg, A. ; Jaarola, M. ; Kugelberg, U. Ö. ; Billiar, T. R. ; Hackam, D. J. ; Sodhi, C. P. ; Breyer, M. D. ; Jakobsson, J. ; Schwaninger, M. ; Schütz, G.DKFZ* ; Parkitna, J. R. ; Saper, C. B. ; Blomqvist, A. ; Engblom, D. (Last author)DKFZ*

2016
ASCJ Ann Arbor, Mich.

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Please use a persistent id in citations: doi:10.1172/JCI83844

Abstract: 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.

Keyword(s): Membrane Proteins ; Receptors, Dopamine D1 ; Cyclooxygenase 1 ; Ptgs1 protein, mouse ; Dinoprostone

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Contributing Institute(s):

1. Helmholtz-Professur Molekularbiologie der Zelle I (A992)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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