Enhanced pelvic responses to stressors in female CRF-overexpressing mice.

Acute stress affects gut functions through the activation of corticotropin-releasing factor (CRF) receptors. The impact of acute stress on pelvic viscera in the context of chronic stress is not well characterized. We investigated the colonic, urinary, and locomotor responses monitored as fecal pellet output (FPO), urine voiding, and ambulatory activity, respectively, in female and male CRF-overexpressing (CRF-OE) mice, a chronic stress model, and their wild-type littermates (WTL). Female CRF-OE mice, compared with WTL, had enhanced FPO to 2-min handling (150%) and 60-min novel environment (155%) but displayed a similar response to a 60-min partial restraint stress. Female CRF-OE mice, compared with WTL, also had a significantly increased number of urine spots (7.3 +/- 1.4 vs. 1.3 +/- 0.8 spots/h) and lower locomotor activity (246.8 +/- 47.8 vs. 388.2 +/- 31.9 entries/h) to a novel environment. Male CRF-OE mice and WTL both responded to a novel environment but failed to show differences between them in colonic and locomotor responses. Male WTL, compared with female WTL, had higher FPO (113%). In female CRF-OE mice, the CRF(1)/CRF(2) receptor antagonist astressin B and the selective CRF(2) receptor agonist mouse urocortin 2 (injected peripherally) prevented the enhanced defecation without affecting urine or locomotor responses to novel environment. RT-PCR showed that CRF(1) and CRF(2) receptors are expressed in the mouse colonic tissues. The data show that chronic stress, due to continuous central CRF overdrive, renders female CRF-OE mice to have enhanced pelvic and altered behavioral responses to superimposed mild stressors and that CRF(1)-initiated colonic response is counteracted by selective activation of CRF(2) receptor.

Corticotropin-releasing factor receptor type 2-deficient mice display impaired coping behaviors during stress.

Two cognate receptors (CRF(1) and CRF(2)) mediate the actions of the stress-regulatory corticotropin-releasing factor (CRF) family of peptides. Defining the respective roles of these receptors in the central nervous system is critical in understanding stress neural circuitry and the development of psychiatric disorders. Here, we examined the role of CRF(2) in several paradigms that assess coping responses to stress. We report that CRF(2) knockout mice responded to a novel setting with increased aggressive behavior toward a bulbectomized conspecific male and show increased immobility during acute swim stress compared with wild-type mice. In addition, CRF(2)-deficient mice exhibited impaired adaptation to isolation stress as evinced by prolonged hypophagia and associated weight loss. Collectively, these results point toward a role for CRF(2) pathways in neural circuits that subserve stress-coping behaviors.

IL-1alpha and TNFalpha down-regulate CRH receptor-2 mRNA expression in the mouse heart.

Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1alpha administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFalpha treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1alpha. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFalpha or IL-1alpha. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions.

Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress.

This review highlights new information gained from studies using recently developed animal models that harbor specific alterations in corticotropin-releasing hormone (CRH) pathways. We discuss features of a transgenic mouse model of chronic CRH overexpression and two mouse models that lack either CRH receptor type 1 (CRH-R1) or type 2 (CRH-R2). Together these models provide new insights into the role of CRH pathways in promoting stability through adaptive changes, a process known as allostasis.

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

Captopril and stress-induced hypertension in the borderline hypertensive rat.

OBJECTIVE: Daily exposure to air-jet stress (AJS) causes sustained elevations of blood pressure in borderline hypertensive rats (BHR). It is known that the renin-angiotensin system is activated during episodes of behavioral stress, and the purpose of this study was to assess the involvement of renin-angiotensin system in the development of stress-induced hypertension in the BHR. DESIGN: Four groups of 8- and 9-week-old rats were studied: they received, respectively, oral captopril and AJS; oral captopril without AJS; AJS without captopril; and neither AJS nor captopril. METHODS: After 10 days of AJS and captopril conditions, femoral and jugular catheters were implanted for the measurement of mean arterial pressure and pressor responses to norepinephrine and tyramine. Blood samples were collected for the measurement of norepinephrine and plasma renin activity. RESULTS: Ten days of AJS caused a significant elevation of blood pressure in BHR exposed to AJS without receiving captopril but not in those animals given captopril concurrently with AJS. Circulating norepinephrine and blood pressure responses to exogenous norepinephrine and tyramine were similar across the four groups. Plasma renin activity was highest in BHR given captopril, and was significantly elevated during an acute episode of AJS. CONCLUSIONS: The renin-angiotensin system may be important in the development of stress-induced hypertension in the BHR.

Stress-induced hypertension in the borderline hypertensive rat: stimulus duration.

Blood pressure and circulating catecholamines were evaluated in borderline hypertensive rats (BHR) that were exposed to daily sessions of either short (20 min) or long (120 min) duration air-jet stimulation. Indirect measures of systolic blood pressure indicated that within 2 weeks both experimental groups developed stress-induced hypertension in comparison to home cage controls. Animals exposed to 120 min stress sessions had significantly higher systolic blood pressure relative to the 20 min group. However, direct measures of blood pressure taken after 5 weeks of daily stress did not reveal any differences between the stress groups. Daily measurements indicated that acute changes in blood pressure during stress were modest and transient, suggesting little contribution to the chronic elevation in blood pressure observed as a consequence of stress. Circulating catecholamines were significantly increased by the stressor. Epinephrine returned to baseline within 60 min, although norepinephrine remained elevated throughout the 120 min session. The results indicate that increasing the duration of daily air jet stimulation did not impact the development of stress-induced hypertension over the 5-week measurement period.