Disruptions in homeostasis (ie, stress) place demands on the body that are met by
the activation of 2 systems, the hypothalamic-pituitary-adrenal (HPA) axis and the
sympathetic nervous system (SNS). Stressor-induced activation of the HPA axis and
the SNS results in a series of neural and endocrine adaptations known as the "stress
response" or "stress cascade." The stress cascade is responsible for allowing the
body to make the necessary physiological and metabolic changes required to cope with
the demands of a homeostatic challenge. Here we discuss the key elements of the HPA
axis and the neuroendocrine response to stress. A challenge to homeostasis (a stressor)
initiates the release of corticotropin-releasing hormone (CRH) from the hypothalamus,
which in turn results in release of adrenocortiotropin hormone (ACTH) into general
circulation. ACTH then acts on the adrenal cortex resulting in release of a species-specific
glucocorticoid into blood. Glucocorticoids act in a negative feedback fashion to terminate
the release of CRH. The body strives to maintain glucocorticoid levels within certain
boundaries and interference at any level of the axis will influence the other components
via feedback loops. Over- or underproduction of cortisol can result in the devastating
diseases of Cushing's and Addison's, respectively, but less severe dysregulation of
the HPA axis can still have adverse health consequences. These include the deposition
of visceral fat as well as cardiovascular disease (eg, atherosclerosis). Thus, chronic
stress with its physical and psychological ramifications remains a persistent clinical
problem for which new pharmacological treatment strategies are aggressively sought.
To date, treatments have been based on the existing knowledge concerning the brain
areas and neurobiological substrates that subserve the stress response. Thus, the
CRH blocker, antalarmin, is being investigated as a treatment for chronic stress because
it prevents CRH from having its ultimate effect-a protracted release of glucocorticoids.
New therapeutic strategies will depend on the discovery of novel therapeutic targets
at the cellular and intracellular level. Advances in molecular biology provide the
tools and new opportunities for identifying these therapeutic targets.
Copyright 2002, Elsevier Science (USA). All rights reserved.