Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

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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.


  • Michael Fritz
  • Anna M. Klawonn
  • Anna Nilsson
  • Anand Kumar Singh
  • Joanna Zajdel
  • Daniel Björk Wilhelms
  • Michael Lazarus
  • Andreas Löfberg
  • Maarit Jaarola
  • Unn Örtegren Kugelberg
  • Timothy R. Billiar
  • David J. Hackam
  • Chhinder P. Sodhi
  • Matthew D. Breyer
  • Markus Schwaninger
  • Günther Schütz
  • Jan Rodriguez Parkitna
  • Clifford B. Saper
  • Anders Blomqvist
  • David Engblom
Enheter & grupper
Externa organisationer
  • Linköping University
  • University of Tsukuba
  • University of Pittsburgh Medical Center
  • Johns Hopkins University
  • Lilly Research Laboratories
  • University of Lübeck
  • German Cancer Research Centre
  • Polish Academy of Sciences
  • Harvard University
  • Beth Israel Deaconess Medical Center

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper
Sidor (från-till)695-705
TidskriftJournal of Clinical Investigation
Utgåva nummer2
StatusPublished - 2015 dec 21
Peer review utfördJa