Central infusion of interleukin-1 receptor antagonist blocks the reduction in social behavior produced by prior stressor exposure

Abstract

Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) in the brain modulate sickness behavior in rodents, in which animals show complex changes in behavior such as the reduction of general activity, reduced social motivation, and fever response. The present studies examined the impact of lipopolysacharide (LPS) and stressor (footshock) exposure on the later expression of social behavior in Sprague-Dawley rats using two separate behavioral paradigms. In Experiment 1, a traditional test for social interaction in which animals were allowed to investigate a juvenile rat in their home cages was conducted at 4 different time points following LPS or footshock treatment. In Experiment 2, social investigation task which allowed the animals to sniff the hole connected to the other chamber where a stimulus animal was placed, but prevented physical contact, was used to measure social investigation at several time points following LPS or footshock treatment. Both systemic infusion of LPS (100 microg/kg) and 2 h footshock exposure (80 shocks, 1 mA, 5 s duration) elicited a time-dependent reduction of social interaction (Experiment 1) and investigation (Experiment 2); LPS-treated rats displayed a more profound reduction of social investigation from 2 h to 6 h after treatment, while rats exposed to footshock showed a reduction 6 h after the footshock exposure. In Experiment 3, the footshock-induced reduction of social investigation was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra; 100 microg icv) infusion. Together, these findings support a growing body of literature showing that stress-dependent changes in brain cytokines play a key role in mediating behavioral consequences of stressor exposure.

Figure 1

A. Rats (n=6 per group) were injected i.p. with vehicle or 100 μg/kg LPS. At 2, 4, 6 and 24 hr after injection, a juvenile conspecific was placed into the cage, and the number of 5 sec intervals during which the adult test subject engaged in social investigation of the juvenile conspecific during a 5 min test was scored. LPS administration to the adult test subjects significantly reduced investigation of a juvenile rat at 2, 4 and 6 hr after injection. * indicates p<.05. B. Rats (n=6-7 per group) were exposed to footshock and returned to their home cages immediately afterwards. At 2, 4 and 6 hr after stressor termination, an unfamiliar juvenile conspecific was introduced into the test subject's home cage for the assessment of social interaction. The number of 5 sec intervals during which the adult test subject engaged in social investigation of the juvenile conspecific during a 5 min test was significantly suppressed at 4 and 6 hr after stressor termination. * indicates p<.05.

Fig. 2

Time-course of the social investigation of rats given 2 hr footshock session (Footshock), or LPS (100μg/kg) injection, or remained in their home cage (Control). The duration (sec) of poking to the social hole (social holes) and the non-social hole (Non-social holes) during 30 min session was counted as the mean ± S.E.M in each time point, baseline and 2, 6, and 24 hr following treatment. Significant differences between treatment groups compared to control in each time point; * p<.05.

Fig. 3

Impact of icv IL-1ra infusion on social investigation of rats given 2-hr footshock session. The duration (sec) of poking to the social hole (social hole) and the non-social hole (Non-social hole) during 30 min session at 4 and 24 hr following the end of footshock session was presented as the mean ± S.E.M. Significant differences between treatment groups ; * p<.05, ** p<.01.