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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

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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 6

Inflammatory aversion is induced by mechanisms different from those triggering inflammatory loss of appetite.

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Inflammatory aversion is induced by mechanisms different from those trig...
(A–D) Food intake 0–6 hours after injection of NaCl or LPS (10 μg/kg, i.p.) in WT mice and mice lacking MyD88 in endothelial cells (Myd88ΔbEnd), mice given the COX-1 inhibitor SC-560, mice lacking mPGES-1, mice lacking EP1Rs, and mice lacking EP1Rs except in D1R-expressing cells (n = 4–9 in each group). (E–G) Aversion scores in response to formalin pain in Myd88ΔbEnd mice (E; n = 10, WT; 12, Myd88ΔbEnd), in mice lacking EP1Rs, and mice lacking EP1Rs but with reexpression in D1R expressing neurons (F; n = 6, Ep1r KO; 6, Ep1r KO resc-D1R) and in Gabrg2 Dat Cre-ERT2 mice (G; n = 7, WT; 5, Gabrg2 Dat Cre-ERT2). (H) Summary of the mechanism proposed to underpin inflammation-induced aversion. Two-way ANOVA (A–D) or Student’s t test (E–G).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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