title: 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.forename: Michael
authors.initials: M
authors.lastname: Fritz
authors.forename: Anna M
authors.initials: AM
authors.lastname: Klawonn
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.forename: Anand Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Joanna
authors.initials: J
authors.lastname: Zajdel
authors.forename: Daniel Björk
authors.initials: DB
authors.lastname: Wilhelms
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.forename: Andreas
authors.initials: A
authors.lastname: Löfberg
authors.forename: Maarit
authors.initials: M
authors.lastname: Jaarola
authors.forename: Unn Örtegren
authors.initials: UÖ
authors.lastname: Kugelberg
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Johan
authors.initials: J
authors.lastname: Jakobsson
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Jan Rodriguez
authors.initials: JR
authors.lastname: Parkitna
authors.forename: Clifford B
authors.initials: CB
authors.lastname: Saper
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
authors.forename: David
authors.initials: D
authors.lastname: Engblom
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D008565:Membrane Proteins; D017447:Receptors, Dopamine D1; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone