Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity

Abstract

Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4 °C, 6 h/day, 14 days) followed on day 15 by a single 1-h session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further, CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD.

Figure 1

Effect of CAPS on active defensive burying behavior and passive immobility in the shock-probe defensive burying test. A) On the shock-probe test, CAPS-treated rats displayed significantly less active burying behavior (29.33 ± 16.77 s) than unstressed control rats (94.67 ± 23.58 s). B) CAPS-treated rats displayed significantly more immobility (167.60 ± 43.98 s) in response to a single, brief mild shock than did the non-stressed controls (33.67 ± 10.39 s). C) Consequently, CAPS-treated rats had a lower bury ratio (0.13 ± 0.10) than control rats (0.67 ± 0.09), reflecting a shift from a predominantly active behavioral coping strategy (ratio > 0.5) in the control group to a predominantly passive strategy (ratio < 0.5) following CAPS treatment. *p < 0.05, **p < 0.01, ***p < 0.001. Data expressed as mean ± SEM, n=9/group.

Figure 2

Effect of CAPS on latency to feed in the novelty suppressed feeding test. A) CAPS-treated rats displayed a longer latency to begin eating (134.3 ± 11.4 s) compared to controls (100.0 ± 6.9 s). B) As expected, CAPS-treated rats had lower mean body weight on test day (281.5 ± 5.3 g) compared to controls (298 ± 5.6 g). C) CAPS-treated rats and control rats consumed an equivalent amount of food during the test (1.35 ± 0.20 g and 1.79 ± 0.20 g, respectively). D) In fact, CAPS-treated rats displayed increased food consumption in the home cage after the test (3.5 ± 0.4 g) compared to control rats (2.3 ± 0.3 g), perhaps related to the reduction in body weight gain during CAPS treatment (panel B). Thus, the increase in latency to feed was not attributable to a loss of appetite, but to an increase in anxiety in the novel environment. *p < 0.05. Latency expressed as mean percent of controls ± SEM. Feeding expressed as mean ± SEM, n = 14–15/grp.

Figure 3

Effect of CAPS on HPA stress reactivity in response to acute immobilization stress. A) CAPS-treated rats displayed a blunted ACTH response to a subsequent acute stressor (bar), particularly in the group tested on day 1 post-CAPS. B) There were no significant differences between groups on the acute CORT response to immobilization stress, although there was a modest decrease in the group tested on day 1 post-CAPS. *p < 0.05 1-day post-CAPS vs Controls, *** p < 0.001 1-day post-CAPS vs Controls, ⁺⁺⁺p < 0.001 1-day post-CAPS vs 5-days post-CAPS. Data expressed as mean ± SEM, n = 7–14/grp.

Figure 4

Lack of effect of a single prior exposure to acute immobilization stress on the subsequent ACTH response to a second immobilization stress. There was no effect of prior immobilization on ACTH release evoked by a second immobilization stress (bar) administered either 1 or 5 days later, suggesting that the effect seen in Fig. 3 was due to CAPS exposure, specifically. Data expressed as mean ± SEM, n= 8–10/grp.