A wide range of stress‐related pathologies such as post‐traumatic stress disorder are thought to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic‐pituitary‐adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to ten days of restraint alone (60 min daily), forced swim alone (30 min daily), or daily sequential exposure to restraint (60 min) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim to sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), and hippocampus (HPC). Sequential exposure to restraint and swim increased IL‐1β in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL‐6 and TNF‐α responses in the HPC and PFC, respectively, that did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL‐1β response evoked by swim exposure imposed immediately after the 6th day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL‐1β response after swim in comparison to acutely‐exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds (a) independent of HPA axis habituation; (b) likely requires more daily sessions of stress to develop; and that (c) IL‐1β displays a greater tendency to habituate after repeated stress challenges than other stress‐reactive cytokines.
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