Activation of serotonergic and noradrenergic neurotransmission in the rat hippocampus after peripheral administration of bacterial endotoxin: involvement of the cyclo-oxygenase pathway.

Abstract

An endotoxic challenge produces pronounced effects on the immune, endocrine and central nervous systems. However, information on the brain structures and neurotransmitter systems participating in the physiological responses after stimulation of the immune system is still scarce. Using an in vivo microdialysis method is conscious, freely moving rats, the present study describes the effects of an endotoxic challenge on hippocampal serotonergic and noradrenergic neurotransmission. Rats were equipped with a microdialysis probe in the hippocampus, which enables the stress-free measurement of extracellular concentrations of serotonin, noradrenaline and their respective metabolites 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol. The behavioral activity was scored by measurement of the time during which rats were active (locomotion, grooming, eating, drinking). In the control rats a significant, positive relationship between the behavioral activity and hippocampal extracellular levels of serotonin, noradrenaline and 3-methoxy-4-hydroxyphenylglycol was found. Intraperitoneally injected bacterial endotoxin (lipopolysaccharide; 100 micrograms/kg body weight) increased extracellular concentrations of serotonin, 5-hydroxyindoleacetic acid, noradrenaline and 3-methoxy-4-hydroxyphenylglycol, whereas the behavioral activity was largely reduced, thus disrupting the correlation between behavioral activity and hippocampal levels of serotonin, noradrenaline and 3-methoxy-4-hydroxyphenylglycol. Intraperitoneal pretreatment of rats with the cyclo-oxygenase inhibitor indomethacin attenuated, but did not completely abolish, the endotoxin-induced increases in hippocampal extracellular levels of serotonin, noradrenaline and their metabolites. From these results it may be concluded that the hippocampal serotonin and noradrenaline neurotransmitter systems are part of the brain circuitry responsive to an endotoxic challenge. Moreover, arachidonic acid metabolites seem to represent important, but not the sole, mediators of the endotoxin-induced changes in hippocampal neurotransmission.