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

Fritz, Michael (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Klawonn, Anna (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Nilsson, Anna (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
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Kumar Singh, Anand (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Zajdel, Joanna (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Wilhelms, Daniel (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Akutkliniken i Linköping
Lazarus, Michael (author)
University of Tsukuba, Japan
Löfberg, Andreas (author)
Linköping University,Linköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten
Jaarola, Maarit (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Örtegren Kugelberg, Unn (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Billiar, Timothy R. (author)
University of Pittsburgh, PA USA,University of Pittsburgh Medical Center
Jakobsson, Johan (author)
Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups,Johns Hopkins University, MD USA,Lund University, Sweden; Lund University, Sweden
Sodhi, Chhinder P. (author)
Johns Hopkins University, MD USA
Breyer, Matthew D. (author)
Lilly Research Labs, IN USA,Eli Lilly and Company
Jakobsson, Johan (author)
Lund University, Sweden; Lund University, Sweden
Schwaninger, Markus (author)
University of Lubeck, Germany
Schuetz, Gunther (author)
German Cancer Research Centre, Germany
Rodriguez Parkitna, Jan (author)
Polish Academic Science, Poland,Institute - Center for Molecular and Macromolecular Studies of the Polish Academy of Sciences
Saper, Clifford B. (author)
Beth Israel Deaconess Medical Centre, MA 02215 USA; Harvard University, MA USA
Blomqvist, Anders (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
Engblom, David (author)
Linköping University,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
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 (creator_code:org_t)
AMER SOC CLINICAL INVESTIGATION INC, 2016
2016
English.
In: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 126:2, s. 695-705
Related links:
http://dx.doi.org/10...
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https://urn.kb.se/re...
https://doi.org/10.1...
https://lup.lub.lu.s...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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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 E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) 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 PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

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