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

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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.",
author = "Michael Fritz and Klawonn, {Anna M.} and Anna Nilsson and Singh, {Anand Kumar} and Joanna Zajdel and {Bj{\"o}rk Wilhelms}, Daniel and Michael Lazarus and Andreas L{\"o}fberg and Maarit Jaarola and {{\"O}rtegren Kugelberg}, Unn and Billiar, {Timothy R.} and Hackam, {David J.} and Sodhi, {Chhinder P.} and Breyer, {Matthew D.} and Johan Jakobsson and Markus Schwaninger and G{\"u}nther Sch{\"u}tz and {Rodriguez Parkitna}, Jan and Saper, {Clifford B.} and Anders Blomqvist and David Engblom",
year = "2015",
month = dec,
day = "21",
doi = "10.1172/JCI83844",
language = "English",
volume = "126",
pages = "695--705",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "Am Soc Clin Investig",
number = "2",