The two systems are not equally activated in response to stress, and recent studies demonstrate that the HPA axis response is stronger to socialevaluative types of stress, while the SNS is stronger in response to stressors causing anxiety and fear. These CPI-613 measures are thus frequently included in stress studies. It can be expected that there is a cross-talk between the two stress systems, i.e. that they interact in relation to the perception and processing of psychosocial stress. However, no systematic studies have looked at this interaction – specifically what happens to one system if the other one failed to respond has to the best of our knowledge not been previously investigated. The aim of the present study was thus to investigate the interaction between the HPA and SNS systems by blocking the acute HPA axis response and then exposing the subject to an acute stressful situation. The research question led to the development of a new stress paradigm: a combination of the dexamethasone suppression test and the TSST, termed “The combined Dexamethasone/TSST paradigm.” The DST is commonly used to test negative feedback inhibition of the HPA axis. As a potent synthetic glucocorticoid, dexamethasone primarily binds to GC receptors in the periphery, and the pituitary, resulting in an almost complete suppression of pituitary release of ACTH for several hours, lasting into the morning following DEX administration the evening before. The lack of ACTH then leads further to almost complete absence of cortisol since the adrenal cortex is not stimulated. It is important to differentiate the effects of a low to moderate administration of DEX between the brain and the periphery. DEX does not cross the blood-brain barrier and thus will not reach receptors above the level of the pituitary in the central nervous system, thus depriving the CNS from any stimulation with glucocorticoids, and causing a hypocorticoid state. In contrast, the amounts typically used in the DST lead to a flooding of receptors in the periphery, causing a hypercorticoid state in the body. In the combined Dexamethasone/TSST paradigm, subjects are exposed to the TSST after DEX has been given the night before, and thus this paradigm allows to test the response of the individual to an acute and strong stressor at the psychological level and the physiological level, in the absence of an HPA axis stress response. Given the role of the HPA system in coping with stress, and the interaction between the different stress systems in the human organism, we hypothesized that the blockade of a cortisol response to acute stress will result in an increased perception of psychological stress, and an increased activity of the SNS. The goal of the present study was investigate the effects of suppressing the HPA axis system in the presence of an acute stressor on blood pressure, heart rate, alpha-amylase, and the subjective experience of stress. In order to do so, we applied an HPA axis suppressant prior to administering acute psychosocial stress.