Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence

Abstract

Interactions among the brain, the pituitary gland, and the adrenal glands (i.e., the hypothalamic-pituitary-adrenal [HPA] axis) help regulate the body's response to stress. The adrenal hormone cortisol plays a key role in stress reduction through its effects on multiple body systems. Excessive cortisol activity during both chronic alcohol administration and withdrawal may underlie some of the clinical complications of alcoholism, including increased risk of infectious diseases; bone, muscle, and reproductive system changes; altered energy metabolism; and disorders of mood and intellect. Despite excessive cortisol levels during intoxication and withdrawal, however, the HPA axis becomes less responsive to stress during abstinence, potentially resulting in an impaired capacity to cope with relapse-inducing stressors.

Figure 1

Location of the components of the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus is located in the brain, directly above the pituitary gland. The adrenal glands are located in the lower back, one atop each kidney.

Figure 2

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Almost any type of stress, including trauma, infection, intense heat or cold, or mental effort, is followed within minutes by increased secretion of cortisol. The occurrence of stress is communicated to the HPA axis by various chemical messengers. The brain monitors and integrates these communications and, when appropriate, activates secretion of corticotropin-releasing hormone (CRH) (and arginine vasopressin [AVP]) from the hypothalamus. These hormones stimulate the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to secrete cortisol. Substances that promote CRH secretion include (among others) stimulatory neurotransmitters (e.g., glutamate), mediators of inflammation (i.e., cytokines), and CRH itself. CRH secretion is decreased by inhibitory neurotransmitters (e.g., gamma-aminobutyric acid [GABA]); in addition, endogenous opioids provide continuous (i.e., tonic) background inhibition of CRH secretion. Of the many chemical messengers that influence secretion of ACTH (by the pituitary) and cortisol (by the adrenal cortex), only serotonin is shown because of its modulatory effect on multiple brain functions. In addition, cortisol modulates its own release (i.e., feedback inhibition), dampening potentially excessive HPA response. The right of the diagram lists selected substances that can be administered to evaluate the responsivity of the HPA axis at various levels. Naloxone suppresses inhibition of CRH secretion by opioids; insulin administration lowers blood sugar, activating ACTH and cortisol secretion (see textbox).