title: Metabotropic glutamate receptors mediate lipopolysaccharide-induced fever and sickness behavior.
abstract: Several mechanisms have been proposed for neuroimmune communication supporting the sickness syndrome (fever, anorexia, inactivity, and cachexia) following infection. We examined the role of glutamate as a neurochemical intermediary of sickness behavior induced by intraperitoneal lipopolysaccharide (LPS). Mice implanted with biotelemetry devices capable of detecting body temperature (Tb) were administered LPS (50 or 500 microg/kg i.p., serotype 0111:B4) with or without i.p. pretreatment with vehicle or broad-spectrum antagonists selective for N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA)/kainite, or metabotropic glutamate (mGlu) receptors. While NMDA and AMPA/kainate receptor antagonism failed to attenuate LPS-induced sickness behavior, antagonism of metabotropic receptors with l(+)-AP3 reduced the febrile (0-11h: control: 37.32+/-0.16 degrees C, l(+)-AP3: 36.66+/-0.27), anorexic (control: -87+/-5%, l(+)-AP3: 48+/-12% scotophase food intake), and cachexic (control: -8.9+/-0.4%, l(+)-AP3: -6.1+/-1.3% body weight) effects of 500 microg/kg LPS, and produced a biphasic Tb effect in response to 50 microg/kg LPS (1h: -0.90+/-0.26; 6h: 1.78+/-0.35 degrees C relative to baseline). At this dose the Tb of l(+)-AP3-treated mice was 1.18 degrees C lower than controls 2h post-injection, and 0.68 degrees C greater that controls 8h post-injection. These results suggest a role for mGlu receptors in mediating fever, anorexia, and cachexia possibly via activation of extra-vagal pathways, since the attenuating effect of l(+)-AP3 increased with increasing dosages of LPS. Given the critical role ascribed to mGlu receptors in neurotransmitter release and astrocytic processes, it is possible that these observations reflect an l(+)-AP3-induced attenuation of these systems.
authors.affiliation: School of Psychological Science, La Trobe University, Bundoora, Vic. 3086, Australia. Tracey.Weiland@svhm.org.au
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Weiland
authors.forename: Debra
authors.initials: D
authors.lastname: Anthony-Harvey-Beavis
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Voudouris
authors.forename: Stephen
authors.initials: S
authors.lastname: Kent
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001831:Body Temperature / Q000276:immunology; D002940:Circadian Rhythm / Q000276:immunology* / Q000502:physiology; D005334:Fever / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012803:Sick Role
chemical_list: D008070:Lipopolysaccharides; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate