The bacterial endotoxin lipopolysaccharide causes rapid inappropriate excitation in rat cortex

There is mounting evidence that inflammation and associated excitotoxicity may play important roles in various neurodegenerative disorders, such as ba cterial infections, Alzheimer's disease, AIDS dementia, and multiple sclero sis. The immunogen E. coli lipopolysaccharide (LPS, endotoxin) has been wid ely used to stimulate immune/inflammatory responses both systemically and i n the CNS. Here, we show that exposure of parietal cortical slices from adu lt rats to LPS triggered very rapid (<2.5 min) and sustained releases of th e neurotransmitters glutamate and noradrenaline, and of the neuromodulator adenosine. The responses to LPS declined rapidly following removal of the L PS and exhibited no tachyphylaxis to repeated exposures to LPS. The detoxif ied form of LPS had no effect. LPS-evoked release of [H-3]noradrenaline, bu t not of glutamate or adenosine, appears to be partly due to the released g lutamate acting at ionotropic receptors on the noradrenergic axons present in the cortical slices. LPS appears to release glutamate, which then acts a t non-NMDA receptors to remove the voltage-sensitive Mg2+ block of NMDA rec eptors, thus permitting NMDA receptors to be activated and noradrenaline re lease to proceed. It seems possible that rapid, inappropriate excitation ma y occur in the immediate vicinity of gramnegative bacterial infections in t he brain. If similar inappropriate excitations are also triggered by those immunogens specifically associated with Alzheimer's disease (beta-amyloid), AIDS dementia (gp120 and gp41), or multiple sclerosis (myelin basic protei n), they might explain some of the acute, transient neurological and psychi atric symptoms associated with these disorders.