Metabotropic glutamate receptors mediate lipopolysaccharide-induced fever and sickness behavior.
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.
Weiland
Tracey J
TJ
School of Psychological Science, La Trobe University, Bundoora, Vic. 3086, Australia. Tracey.Weiland@svhm.org.au
Anthony-Harvey-Beavis
Debra
D
Voudouris
Nicholas J
NJ
Kent
Stephen
S
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
D008070:Lipopolysaccharides; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate