Alteration of Locus coeruleus Neuronal Activity by Interleukin-1 and the Involvement of Endogenous Corticotropin-Releasing Hormone

Abstract

Activity of the locus coeruleus (LC), which is the source of most of the norepinephrine in the brain, may participate in effects of the cytokine interleukin (IL)-1. This report describes the influence of IL-1 beta on the electrophysiological single-unit activity of LC neurons. When microinjected into the LC, human recombinant IL-1 beta (50 pg to 5 ng) increased the activity of LC neurons, predominantly by increasing 'burst' firing, which occurs in response to a sensory stimulus. At the higher doses and/or with longer time delays after injection, the spontaneous depolarization rate was also increased. This excitation (1). did not occur if IL-1 beta was microinjected nearby but outside of the LC and (2). could be reversed by administration of IL-1 receptor antagonist (IL-1 RA). In contrast to excitatory effects, microinjection of a very low dose of IL-1 beta (5 pg) into the LC inhibited LC activity, and this change could also be blocked by IL-1 RA. In view of earlier findings that (1). LC electrophysiological activity could be inhibited by microinjection of corticotropin-releasing hormone (CRH) into the LC region and (2). IL-1 beta in the brain stimulates the release of CRH, the hypothesis was tested that the inhibition of LC activity produced by the low dose of IL-1 was mediated by CRH. Microinfusion of the CRH receptor antagonist alpha-helical CRH(9-41) blocked the inhibition of LC activity otherwise produced by 5 pg of IL-1 beta, thus indicating that IL-1 beta also influences the activity of LC neurons via CRH. Finally, microinjection of IL-1 RA alone was found to decrease LC activity, raising the possibility that LC neurons are under the influence of tonic excitation by IL-1 in the brain. In summary, the findings described here show that the activity of LC neurons can be influenced by IL-1 beta through stimulation of IL-1 beta receptors. The potential involvement of IL-1 beta in stress responses by means of this cytokine influencing the activity of LC neurons is discussed.