NEURAL AND BIOCHEMICAL MEDIATORS OF ENDOTOXIN AND STRESS-INDUCED C-FOS EXPRESSION IN THE RAT-BRAIN

We and others have reported that c-fos protein is induced in the hypot halamus and brain stem of the rat following central and peripheral inj ections of endotoxin (lipopolysaccharide; LPS). We have now examined p ossible mechanisms through which LPS induces c-fos protein. The cyclox ygenase inhibitor indomethacin and the glutamate NMDA antagonist MK801 inhibited c-fos protein in the paraventricular nucleus (PVN), supraop tic nucleus (SON), and the A1/A2 regions of the brain stem induced by IP or IV injections of LPS (40 mu g). The H1 histamine antagonist diph enhydramine, but not the H2 histamine antagonist cimetidine, reduced t he amount of c-fos labeling. MK801 also attenuated the effects of stre ss (foot shock) on c-fos protein; however, indomethacin had no effect on c-fos protein induced by stress. We next examined the importance of visceral afferent innervation on the response to LPS or stress. Subdi aphragmatic vagotomy completely blocked the induction of c-fos protein following IP injections of LPS; however, vagotomy had a minimal effec t on c-fos protein induced in the PVN and SON following IV injections of LPS, but potentiated c-fos induction following foot shock. Thus, pr ostaglandin synthesis, glutamate release, histamine receptors, and vis ceral afferents represent functional biochemical and neural pathways t hrough which endotoxin activates c-fos protein in specific autonomic a nd neuroendocrine regulatory nuclei. Activation of NMDA glutamate rece ptors may represent a final common pathway for the induction of c-fos protein in the brain induced by both endotoxin and stress.