Abstract: The “cytokine theory of depression” indicated that cytokines induced by immunity activity are not only immunity mediators but also play an important role in the mechanism of depressive-like behaviors. The administration of lipoposaccharide (LPS), which is a product of the cell wall of gram-negative bacteria, is known to activate immune functions and induce the release of several cytokines both in the periphery, and the brain such as frontal cortex, hippocampus, and hypothalamus that are considered to be the essential brain regions of depression. Many studies found that the administration of LPS could induce depressive-like behavior, such as a decrease in the preference of sweet milk, low locomotion, and anorexia. However, these researches only pay attention to short-term behavior effects; the effects of LPS administration on long-term behavior changes have not been clearly reported. To further understand the role of immunity activation-induced cytokines in depression, the purpose of the present study was to investigate the effects of repeated administration of LPS in different doses on behavior and the long-term behavior effects in rats.
Method
Fifty rats were randomly divided into 4 LPS groups (LPS400, LPS200, LPS50, and LPS10) and 1 saline control group (LPS0); each group comprised ten rats. According to the groups, the rats were injected intraperitoneally with LPS 400 μg/kg, 200 μg/kg, 50 μg/kg, 10 μg/kg, and saline, respectively; they were injected again after 3 days. Two hours, 24 hours, and 48 hours after every injection, the rats were subjected to a saccharin preference test, an open-field test, and an elevated plus-maze test.
Results
The results indicated that 2 hours after the first LPS injection, the percent of saccharin preference, locomotion and upright activity in the open-field test, and open arms and closed arms entries in the elevated plus-maze test were significantly lower in LPS50, LPS200, and LPS400 than in the saline control group (percent of saccharin preference: p < 0.01; locomotion: p < 0.01; upright activity: p < 0.01; open arms entries: p < 0.01; and closed arms entries: p < 0.01). It was also found that the LPS-treated rats had fewer open arms entries than the saline controls 2 hours after the repeated LPS injection (p < 0.01). However, there was no significant difference between the LPS-treated groups and the saline control group with respect to behavior changes 24 hours and 48 hours after the first LPS injection and after the repeated LPS injection. In addition, there were no differences among LPS400, LPS200, and LPS50 at any given point of time.
Conclusions
Our results demonstrate that LPS-induced immunity activation can result in evident depressive-like behavior in animals. However, no significant long-term effect in behavior was found. Thus, the present results suggest that LPS-induced proinflammation cytokines may be one of the conditions, but not the only condition or sufficient condition that causes the long-term depression. Using the animal model of LPS-induced depression has certain limitations.

Key words: lipoposaccharide, depressive-like behavior, anhedonia, locomotion