Our organism is daily subjected to environmental changes that challenge body homeostasis. These changes are often perceived as stressors, with which the body copes via physiological and metabolic adaptive responses. Activation of the ‘stress system’ leads to behavioral and hormonal changes that improve the ability of the organism to adjust a state of ‘threatened’ homeostasis and increase its chances of survival. Among the endocrine/neuroendocrine tissues involved in the homeostatic response to stress, the adrenal glands are probably the most emblematic and best known to the general public. Who does not know the word ‘adrenaline’? Who has never experienced an adrenaline rush during a stress episode? Behind stress-induced adrenaline release are intricate and complex regulatory mechanisms that prepare the body to fight or flight.

Let us begin this review with a brief introduction to the history of the biological concept of stress. A recognized founding father of the concept of stress is Hans Selye with his description of the ‘General Adaptation Syndrome’ (GAS). However, the history of the biology of stress begins earlier with the fundamental studies of James Reilly on the pathogenesis of many diseases (Hopkin & Laplane, 1978). Reilly was the first in the 1930s to demonstrate experimentally the unambiguous, non-specific response to infections of various origins, and the primary role of the sympathetic nervous system. Unlike Selye, the international dissemination of his work has been more modest. For the record, Reilly described intense reactions in response to bacterial products in certain animals, leading to death without being able to speak of an infection, and showed that the primary damage to the organism does not take place where the organic disorders appear, but targets the autonomic nervous system. From this nervous pathway, the damage is transmitted to more or less distant tissues/organs, where it is occurred secondarily. From this finding, James Reilly described the ‘simple disease state syndrome’, a multivalent syndrome occurring in any disease, better known as Reilly’s syndrome. At the same time, Hans Selye works on rats exposed to noxious stimuli, and in a short note published in Nature in 1936, he established the concept of GAS and gave a definition (Selye, 1936). In this note, Selye wrote “.... if the organism is severely damaged by acute non-specific nocuous agents such as...., a typical syndrome appears, the symptoms of which are independent of the nature of the damaging agent or the pharmacological type of the drug employed, and represent rather a response to damage as such”. GAS consists in three sequential steps, the alarm, resistance and exhaustion phases. In each of these, the adrenal glands, and the adrenomedullary tissue in particular, are critically involved.

The adrenal glands are composed of a double endocrine/neuroendocrine tissue, which encompasses the cortical and medullary zones. The adrenal cortex is activated by the hypothalamo-pituitary-adrenocortical axis and releases corticosteroids (mainly glucocorticoids). Increased levels of glucocorticoids induce anabolism processes that maintain or increase glycemia. Interestingly, adrenocortical secretions also impact the secretory activity of adrenomedullary chromaffin cells. The adrenomedullary tissue, which is mostly composed of chromaffin cells, contributes to maintain body homeostasis in reaction to stressful environmental changes via the release of catecholamines (mainly epinephrine) into the blood circulation in response to splanchnic nerve activation. By far, the largest reservoir of epinephrine in the body comes from adrenal chromaffin cells. Catecholamine secretion from adrenal chromaffin cells occurs via a mechanism initially described by W.W. Douglas (1968) and called ‘stimulus-secretion coupling’. The initial stimulus comes from the sympathetic nervous system that releases acetylcholine at splanchnic nerve terminals synapsing onto chromaffin cells (Douglas, 1968, Wakade, 1981) and reviewed in (Carbone et al., 2019, Guerineau, 2020). This traditional view of stimulus-secretion coupling, with electrical discharges invading the splanchnic nerve endings as the only physiological stimulus triggering catecholamine release in vivo, prevailed during many decades. It was expanded in the early 2000s when a gap junction-mediated coupling between chromaffin cells entered the fray as a novel protagonist involved in catecholamine release (Martin, Mathieu, Chevillard, & Guerineau, 2001). Indeed, studies performed both in acute adrenal slices and in anaesthetized rodents revealed that the local communication mediated by gap junctions between chromaffin cells represents a functional route by which biological signals (electrical activity, second messengers) propagate between adjacent cells and subsequently generate instructive signals to trigger hormone secretion (Desarmenien et al., 2013, Martin et al., 2001).

At rest, these two signaling pathways are in equilibrium and the adrenal secretion of catecholamines is minimal. Stress challenges this homeostasis, either briefly for an acute stress or more robustly for a chronic stress, but in all cases, stress triggers a huge secretion of catecholamines. This cannot be properly achieved without the remodeling of the adrenomedullary stimulus-secretion coupling. Here, I propose to review the adaptive mechanisms that take place in the stressed adrenal medulla, but because the elementary components of the stimulation-secretion coupling are quite a few, the choice has been made to focus on only some of them. The author apologizes for those that are not covered in this chapter. I also apologize to those authors contributing to this field, whose articles were not cited because of space limitations.