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


Mark K. Borsody, MD, PhD, or Jay M. Weiss, PhD, Department of Psychiatry and Behavioral Sciences, Emory University, Emory Briarcliff Campus, 1256 Briarcliff Road NE, Atlanta, GA 30306, USA. Tel: + (404) 712–9771; Fax: + (404) 712–9755; E-mail:


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.