Influence of the estrous cycle on tolerance development to LPS-induced sickness behaviors in rats

The relations between the estrous cycle, inflammatory responses and the development of tolerance to endotoxin were examined. Female Long-Evans rats were injected intraperitoneally with lipopolysaccharide (LPS; 200 microg/kg) or saline vehicle at 08:00h on either diestrus (D) or proestrus (P). Ninety-five minutes after injection locomotor activity was assessed in an automated non-novel open-field for 20 min. To assess tolerance development to LPS, rats were re-injected at the next identical stage (i.e. 4 days later; groups: DD, PP) or at the alternate stage (i.e. 6 days later; groups: DP, PD) of the estrous cycle and locomotor activity was again assessed. On Test Day 1 all groups injected with LPS exhibited similar significant activity decrements, regardless of the stage of the estrous cycle. However, on Test Day 2 rats which received both injections of LPS during proestrus (PP) showed no signs of tolerance development, whereas rats in all other groups were tolerant to LPS. In a follow up study, the time between injections was extended to 8 days. Still the animals injected both times at proestrus showed no signs of tolerance to LPS after the second injection. Thus, the stages of the estrous cycle both at the time of initial exposure and of re-exposure appear critical in the formation of behavioral tolerance to LPS in rats.