Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice.
Endotoxin (LPS) administration has been shown to activate the hypothalamo-pituitary-adrenocortical (HPA) axis and increase cerebral catecholamine and indolamine metabolism and tryptophan concentrations. LPS stimulates the secretion of tumor necrosis factor-alpha (TNF-alpha) as well as interleukin-1 and interleukin-6. We have investigated the role of TNF-alpha in the LPS-induced neurochemical and neuroendocrine changes. When recombinant mouse TNF-alpha (mTNF-alpha) was injected intraperitoneally (i.p.) into mice, plasma corticosterone concentrations were elevated reaching a peak at 30 min. Two hours after injection, cerebral tryptophan concentrations were also elevated in several brain regions, as well as the ratio of brain 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to norepinephrine (NE) in the hypothalamus. An intravenous (i.v.) injection of mTNF-alpha also increased cerebral tryptophan concentrations and MHPG/NE ratios at 2 h and caused a rapid and prolonged elevation of plasma corticosterone concentrations lasting for at least 2 h. We observed no significant changes in dopamine or its catabolites, or in 5-hydroxytryptamine or its major catabolite, 5-hydroxyindoleacetic acid, after either i.p. or i.v. injections. These results suggest that TNF-alpha may contribute to the HPA, neurochemical and behavioral responses to LPS and other stimulators of the immune system.
Ando
T
T
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, LA 71130-3932, USA.
Dunn
A J
AJ
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014364:Tryptophan; D003345:Corticosterone; D009638:Norepinephrine