title: Adenosine through the A2A adenosine receptor increases IL-1β in the brain contributing to anxiety.
abstract: Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by 2-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain.
authors.affiliation: Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Chiu
authors.affiliation: Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Darmody
authors.affiliation: Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.affiliation: Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Moon
authors.affiliation: Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Kwakwa
authors.affiliation: Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Bray
authors.affiliation: Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Animal Sciences, University of Illinois, Urbana, IL, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: McCusker
authors.affiliation: Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA; Department of Animal Sciences, University of Illinois, Urbana, IL, USA. Electronic address: freun@illinois.edu.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Freund
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000633:toxicity*; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D020170:Caspase 1 / Q000172:deficiency / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D054086:KATP Channels / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000502:physiology
chemical_list: D002227:Carbazoles; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D054086:KATP Channels; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D043705:Receptor, Adenosine A2A; D053573:Receptors, Interleukin-1 Type I; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D020170:Caspase 1; D000241:Adenosine; D011188:Potassium; D005905:Glyburide
keywords: Adenosine receptor; Anxiety; Caspase-1; Interleukin-1