Although accumulating evidence supports a role for cytokines in the pathophysiology of depression, the cytokine hypothesis of depression is debatable. It has been suggested that neuroendocrine and immune systems acting in concert may have roles in the development and the maintenance of the disease. Glucocorticoid receptor (GR) is the key element which exerts both anti-inflammatory and cytokineinhibiting effects. Whether functional changes of GR are involved in the pathophysiology of cytokineinduced depression remains elusive. In the present study, the effects of both acute and chronic GR blockade on depressive-like behaviour and cytokine production induced by lipopolysaccharides (LPS), cytokine inducer, were investigated in rats. Acute or chronic blockade of GR was achieved by a single administration or repeated administrations, respectively, of the GR antagonist RU486 (RU). Behavioural measurements, including saccharin preference, locomotor activity, and immobility time, were assessed. The serum levels of proinflammatory cytokines (TNFa, IL-1b, and IFNc) were determined by ELISA. The results showed that LPS induced significant but transient depressive-like behaviour. Repeated, but not single, administration of RU significantly enhanced and prolonged LPS-induced depressive-like behavior and an increase in the serum production of TNFa and IFNc. These results indicate that the effective blockade of GR enhanced the depressive-like behaviour induced by cytokines. Findings from this study suggest that GR dysfunction may be an important contributing factor to the development of cytokine-related depression. These findings add to the growing evidence of mechanisms by which cytokines influence depression.