Predator Scent-Induced Sensitization of Hypertension and Anxiety-like Behaviors

Abstract

Post-traumatic stress disorder (PTSD), an anxiety-related syndrome, is associated with increased risk for cardiovascular diseases. The present study investigated whether predator scent (PS) stress, a model of PTSD, induces sensitization of hypertension and anxiety-like behaviors and underlying mechanisms related to renin-angiotensin systems (RAS) and inflammation. Coyote urine, as a PS stressor, was used to model PTSD. After PS exposures, separate cohorts of rats were studied for hypertensive response sensitization (HTRS), anxiety-like behaviors, and changes in plasma levels and mRNA expression of several components of the RAS and proinflammatory cytokines (PICs) in the lamina terminalis (LT), paraventricular nucleus (PVN), and amygdala (AMY). Rats exposed to PS as compared to control animals exhibited (1) a significantly greater hypertensive response (i.e., HTRS) when challenged with a slow-pressor dose of angiotensin (ANG) II, (2) significant decrease in locomotor activity and increase in time spent in the closed arms of a plus maze as well as general immobility (i.e., behavioral signs of increased anxiety), (3) upregulated plasma levels of ANG II and interleukin-6, and (4) increased expression of message for components of the RAS and PICs in key brain nuclei. All the PS-induced adverse effects were blocked by pretreatment with either an angiotensin-converting enzyme antagonist or a tumor necrosis factor-α inhibitor. The results suggest that PS, used as an experimental model of PTSD, sensitizes ANG II-induced hypertension and produces behavioral signs of anxiety, probably through upregulation of RAS components and inflammatory markers in plasma and brain areas associated with anxiety and blood pressure control.

Keywords: Behavior; Blood pressure; Inflammation; Predator scent stress; Renin–angiotensin system.

Fig. 1

Pressor effects (Fig. 1a and b) and heart rate (HR) (Fig. 1c and d) changes induced by angiotensin (ANG) II in control, coyote urine scent-exposed, and coyote urine scent-exposed plus pretreatment plus either captopril (Cap) or pentoxifylline (PTX) rats. The enhanced pressor effect in coyote urine scent-exposed rats was attenuated by either Cap or PTX pretreatment. Baseline recordings are denoted by B’s. (n = 7–10/group; *p < 0.05 vs baseline; ^#p < 0.05 vs control or coyote urine scent-exposed rats plus Cap or PTX pretreatment; ^ǂp < 0.05 vs coyote urine scent-exposed or coyote urine scent-exposed rats with PTX pretreatment; ^§p < 0.05 vs control, coyote urine scent-exposed or coyote urine scent-exposed rats with PTX pretreatment)

Fig. 2

Locomotor activity changes (Fig. 2a and b) induced by coyote urine scent exposure in rats with normal drinking water or pretreated with either captopril (Cap) or pentoxifylline (PTX). Coyote urine scent exposure significantly reduced rat locomotor activity in all groups. Baseline activity is denoted by B’s. (n = 7–10/group; *p < 0.05 vs baseline; ^#p < 0.05 vs normal drinking water or pretreatment with PTX)

Fig. 3

Assessment of anxiety-like behavior in control or coyote urine scent-exposed rats given either normal drinking water or an ACE inhibitor (captopril, Cap) or a TNF-α inhibitor (pentoxifylline, PTX) in the drinking water, including time in the closed arms (Fig. 3a), time in the open arms (Fig. 3b), and entries in the closed or open arms (Fig. 3c). (n = 9–16/group; *p < 0.05 vs. control rats; ^#p < 0.05 vs. coyote urine scent-exposed rats)

Fig. 4

Quantitative comparison of the mRNA expression of renin–angiotensin system components, proinflammatory cytokines, and microglial marker in the lamina terminalis (LT, Fig. 4a), paraventricular nucleus (PVN, Fig. 4b), and amygdala (AMY, Fig. 4c) in control, coyote urine scent-exposed, coyote urine scent-exposed, and pretreatment with either captopril (Cap) or pentoxifylline (PTX) rats before angiotensin II infusion. (n = 5–7/group; *p < 0.05 vs control rats; ^#p < 0.05 vs. coyote urine scent-exposed rats without pretreatment).

Fig. 5

Plasma levels of renin–angiotensin system component (angiotensin II, ANG II, Fig. 5a), proinflammatory cytokine (interleukin-6, IL-6, Fig. 5b) in control, coyote urine scent-exposed, coyote urine scent-exposed plus pretreatment with either captopril (Cap) or pentoxifylline (PTX) rats before ANG II administration. The elevated plasma levels of ANG II or IL-6 in coyote urine scent-exposed rats were attenuated by either Cap or PTX pretreatment. (n = 8–12/group; *p < 0.05 vs. control rats; ^#p < 0.05 vs. coyote urine scent exposed without pretreatment)

Fig. 6

Schematic representation of predator scent (PS) stress-elicited hypertensive response sensitization (HTRS) and anxiety-like behaviors through upregulation of renin–angiotensin system (RAS) and inflammatory cytokines (PICs) in peripheral and central nervous system (CNS) network controlling blood pressure (BP) and behaviors including the lamina terminalis (LT), paraventricular nucleus of hypothalamus (PVN), and amygdala (AMY)