The role of the AMPA receptor and 5-HT(3) receptor on aggressive behavior and depressive-like symptoms in chronic social isolation-reared mice.

Chronic social isolation (SI)-reared mice exhibit aggressive and depressive-like behaviors. However, the pathophysiological changes caused by chronic SI remain unclear. The hypothalamus and amygdala have been suggested to be associated with the stress of SI. In addition to serotonin 3 (5-HT3) receptors, AMPA receptors have also been suggested to be involved in aggressive behavior and depressive-like symptoms in animals. Therefore, we examined whether chronic SI affects AMPA and 5-HT3 receptor expression levels in these regions. A Western blot analysis revealed that after four weeks of SI, mice exhibited up-regulated AMPA receptor subunit (GluR1, GluR2) protein levels in the amygdala and down-regulated hypothalamic 5-HT3 receptor protein levels. The AMPA/kainate receptor antagonist NBQX (10 mg/kg; i.p.) attenuated SI-induced depressive-like symptoms but not aggressive behavior. Intra-amygdalar infusions of the selective AMPA receptor agonist (S)-AMPA (10 µM) induced despair-like behavior, but not sucrose preference or aggressive behavior, in mice not reared in SI (naïve mice). Alternatively, treatment with the 5-HT3 receptor agonist SR57227A (3.0 mg/kg; i.p.) decreased aggression levels. In addition, intra-hypothalamic infusions of the 5-HT3 receptor antagonist ondansetron (3 µM) did not trigger aggressive behavior in naïve mice; however, the administration of ondansetron (0.3 mg/kg; i.p.) increased aggression levels in two-week SI mice, which rarely exhibited the aggressive behavior. Moreover, ondansetron did not affect the depressive-like symptoms of the SI mice. These results suggest that SI-induced up-regulation of GluR1 and GluR2 subunits protein levels in the amygdalar region and down-regulation of 5-HT3 receptor proteins level in the hypothalamic region are associated with the effect of AMPA receptor agonist and 5-HT3 receptor antagonist -induced aggressive behavior and depressive-like symptoms.

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

RATIONALE: Many studies have supported the cytokine hypothesis as the underlying pathophysiology of depressive disorder. OBJECTIVES: 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. METHODS: Adult male CD1 mice were treated with LPS (1 mg/kg, i.p.) or saline and sacrificed 2 h 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)-1ß (0.5 µg), IL-6 (1 µg), or tumor necrosis factor (TNF)-α (1 µg), and sacrificed 2 h 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 (5 µg) or phenylephrine (40 µg). These effects were countered by i.c.v. administration of prazosin and a leptin antagonist. RESULTS: LPS increased c-fos expression in TH-positive neurons. Central administration of IL-6 and IL-1ß 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-1ß and IL-6 was prevented by pretreatment with prazosin alone. CONCLUSION: These results suggest that IL-6-dependent LC neuronal activation induced depression-like behavior and IL-1ß-induced increase in leptin levels enhanced α1-adrenoceptor-mediated depression-like behavior.