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-α (TNF-α) as well as interleukin-1 and interleukin-6. We have investigated the role of TNF-α in the LPS-induced neurochemical and neuroendocrine changes. When recombinant mouse TNF-α (mTNF-α) 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-α 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-α may contribute to the HPA, neurochemical and behavioral responses to LPS and other stimulators of the immune system.

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