Lipopolysaccharide-induced hypoactivity and behavioral tolerance development are modulated by the light-dark cycle in male and female rats

Rationale: Although the behavioral effects of systemic injection of lipopolysaccharide (LPS) have been extensively investigated, the modulation of these effects by natural environmental factors has received little attention. Objectives: The present study investigated whether or not locomotor activity reductions and the development of behavioral tolerance in response to LPS treatment would occur to the same degree if male and female rats were treated with LPS at four distinct time points across the light-dark (LD) cycle. Methods: On day 1, male and female rats were injected with either LPS (200 μg/kg IP) or saline at light onset (0400 hours), 2 h into light period (0600 hours), at dark onset (1600 hours) or 2 h into the dark period (1800 hours). Two hours after injection, rats were placed in non-novel, automated open-fields and locomotor activity was assessed. The development of behavioral tolerance to LPS was evaluated three days later (day 4) using the same procedure. Results: On day 1, LPS-treated animals displayed robust activity decrements during the light period with males displaying greater reductions than females. During the dark period, LPS-treated animals showed a similar hypoactivity response. After LPS treatment on day 4, all rats exhibited some behavioral tolerance to LPS. Rats given LPS treatment at light onset and during the dark period showed complete tolerance development while LPS-treated rats during the light phase at dark onset showed incomplete tolerance, still displaying significant reductions in some activity variables. Conclusions: It appears that the magnitude of hypoactivity and the development of behavioral tolerance in response to LPS depend on the phase of the LD cycle during which it is administered.