2 Neuroscience2.8 Modulators, hormones and inflammatory responses
2.8.2 Stress response and effects of glucocorticoids
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Written by Resident Doctor Committee · Published
Two speeds of response
Catecholamines act within seconds: sympathetic nerves release noradrenaline and the adrenal medulla secretes adrenaline.
Cortisol follows over minutes and lasts longer. Its synthesis from cholesterol takes minutes, and it is not stored in vesicles.
The hypothalamic-pituitary-adrenal (HPA) axis
Level | Role |
|---|---|
Hypothalamus, paraventricular nucleus | Releases corticotrophin-releasing hormone and vasopressin into portal blood |
Anterior pituitary | Releases adrenocorticotrophic hormone (ACTH) |
Adrenal cortex, mainly zona fasciculata | Synthesises and secretes cortisol |
Liver | Inactivates cortisol |
Only the adrenal cortex makes cortisol: the hypothalamus and pituitary drive it, and the adrenal medulla makes catecholamines.
Cortisol feeds back to reduce ACTH and hypothalamic drive.
Corticosteroid receptors
Feature | Type I, mineralocorticoid | Type II, glucocorticoid |
|---|---|---|
Affinity | High | Lower |
Occupancy | Largely filled at basal levels | Fills at the circadian peak and in stress |
Roles | Baseline excitability, initial response | Energy, memory, ending the response |
Drugs acting on the axis
Drug | Action |
|---|---|
Mifepristone | Antagonist at the type II glucocorticoid receptor and the progesterone receptor |
Dexamethasone | Glucocorticoid receptor agonist |
Spironolactone | Blocks the type I mineralocorticoid receptor |
Metyrapone, ketoconazole | Inhibit cortisol synthesis |
Mifepristone was studied in depression with HPA axis overactivity, including psychotic depression, where it remains investigational.
Sustained exposure
In the hippocampus, dendrites retract and dentate neurogenesis falls, weakening contextual memory and feedback.
In the prefrontal cortex, working memory and top-down control decline, while the amygdala grows more responsive.
Allostatic load (McEwen) is the cumulative cost of adaptation from frequent stressors, failed habituation or delayed termination.