Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
Michael Fritz, … , Anders Blomqvist, David Engblom
Michael Fritz, … , Anders Blomqvist, David Engblom
Published December 21, 2015
Citation Information: J Clin Invest. 2016;126(2):695-705. https://doi.org/10.1172/JCI83844.
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Research Article Neuroscience

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

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.

Authors

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, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom

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Figure 3

Inflammation-induced aversion is dependent on cerebral PGE2 synthesis.

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Inflammation-induced aversion is dependent on cerebral PGE2 synthesis. (...
(A) Place avoidance in mice pretreated i.p. with NaCl (n = 7), the unspecific COX inhibitor indomethacin (Indo; n = 8), the COX-2–specific inhibitor parecoxib (n = 5), or the COX-1–specific inhibitor SC-560 (n = 6). (B) Aversion in mice lacking COX-1 (Cox1 KO) or COX-2 (Cox2 KO). Aversion is intact in WT mice (n = 6) and mice lacking COX-2 (n = 6) but blocked in mice lacking COX-1 (n = 8). (C) LPS-induced aversion in mice given i.c.v. injections with NaCl (n = 8) or SC-560 (n = 6) during conditioning. (D) Mice lacking mPGES-1 (mPGES1 KO) display a significantly reduced avoidance of the LPS-paired chamber as compared with WT mice (n = 7, WT; 6, mPGES1 KO). (E–H) Aversion scores from mice lacking PGE2 receptors of type EP1–4. Aversion is significantly blunted in mice lacking EP1Rs (n = 7, WT; 8, Ep1r KO) (E) and EP2Rs (n = 8, WT; 8, Ep2r KO) (F) but not in mice lacking EP3Rs (n = 6, WT; 6, Ep3r KO) (G), or EP4Rs (n = 8, WT; 4, Ep4r-ΔCNS; control group shared with EP2) (H). *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA followed by Dunnett’s post hoc test (A and B) or Student’s t test (C–H).