The development of depression-like behavior is consolidated by IL-6-induced activation of locus coeruleus neurons and IL-1β-induced elevated leptin levels in mice

Abstract

Many studies have supported the cytokine hypothesis as the underlying pathophysiology of depressive disorder. We previously reported that lipopolysaccharide (LPS)-induced depression-like behavior is abrogated by the α1-adrenoceptor antagonist prazosin. Since cytokines are involved in LPS effects on the brain, we investigated the effects of cytokines on noradrenergic neurons in the locus coeruleus (LC) and whether central α1-adrenoceptors can cause the development of depression-like behavior. Adult male CD1 mice were treated with LPS (1mg/kg, i.p.) or saline and sacrificed 2h later for immunofluorescence studies of c-fos and tyrosine hydroxylase (TH) expression in LC neurons. Serum cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Another group of mice were implanted with intracerebroventricular (i.c.v.) cannulae and given artificial cerebrospinal fluid (CSF) (control), interleukin (IL)-1β (0.5μg), IL-6 (1μg), or tumor necrosis factor (TNF)-α (1μg), and sacrificed 2h later for c-fos and TH immunofluorescence analysis. Serum samples were analyzed for leptin levels. In addition, tail suspension test (TST), forced swimming test (FST), and sucrose preference (SP) test were conducted in a separate group of mice treated i.c.v. with cytokines, recombinant mouse leptin (5μg) or phenylephrine (40μg). These effects were countered by i.c.v. administration of prazosin and a leptin antagonist. LPS increased c-fos expression in TH-positive neurons. Central administration of IL-6 and IL-1β increased c-fos immunoreactivity and serum leptin levels. Phenylephrine, an α1-adrenoceptor agonist, given i.c.v., increased the immobility time during FST and decreased SP, but had no effect on TST. Central leptin administration increased immobility time during FST but did not affect TST or SP. The combination of phenylephrine and leptin increased immobility time during FST and TST, and decreased SP. Induction of depression-like behavior by co-administration of IL-1β and IL-6 was prevented by pretreatment with prazosin alone. These results suggest that IL-6-dependent LC neuronal activation induced depression-like behavior and IL-1β-induced increase in leptin levels enhanced α1-adrenoceptor-mediated depression-like behavior.