Peripheral endotoxin causes long-lasting changes in locus coeruleus activity via IL-1 in the brain

Activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group in the brain whose axons give rise to approximately 70% of norepinephrine (NE) in the brain, is believed to play an important role in attention/vigilance, cognitive functions and behavioral disorders, particularly depression. Results described here show that in the rat, intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, a bacterial endotoxin) causes long-lasting changes in electrophysiological activity of LC neurons that are mediated by interleukin-1 (IL-1) acting locally in the LC region. First, it was found that IL-1, when microinjected into the LC region or stimulated/expressed in that brain region, increased activity of LC neurons. The only exception to this was that a very low dose of microinjected IL-1 (5 pg) decreased LC activity, which could be blocked by an antagonist to corticotropin-releasing hormone (CRH), thus suggesting that the decrease was due to IL-1 stimulation of CRH release. All of these effects could be blocked by injection and/or infusion of IL-1 receptor antagonist (IL-1RA) specifically into the LC region. Next, intraperitoneal (i.p.) injection of a low dose of LPS(10 µg/kg or 100 ng/kg) was also found to increase LC activity. The excitation of LC produced by 10 µg/kg i.p. LPS increased progressively for at least 1 week, with LC neurons firing at more than twice their normal rate at 1 week after the i.p. LPS injection. Alteration of LC activity lasted for 3 weeks after a single i.p. injection of 10 µg/kg LPS. The effects of i.p. LPS on LC activity at any time after i.p. injection could be blocked by a brief microinfusion of IL-1RA into the LC region, thereby indicating that changes in LC activity seen after the i.p. LPS were caused by IL-1 acting in the LC region. Finally, i.p. injection of peptidoglycan, representing gram-positive bacteria, and polyinsinic-polycytidylic acid [poly(I):(C)], representing viral infection, also caused increases in LC activity, and the effects of peptidoglycan [but not those of poly(I):(C)] were blocked by microinfusion of IL-1RA into LC. These findings suggest that bacterial infections can give rise to prolonged changes in brain activity through cytokine action in brain.