Disturbances of the Stress Response The Role of the HPA Axis During Alcohol Withdrawal and Abstinence Bryon Adinoff, M.D., Ali Iranmanesh, M.D., Johannes Veldhuis, M.D., and Lisa Fisher, Ph.D. 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. KEY WORDS: AOD withdrawal syndrome; physiological stress; hypothalamic-pituitary axis; pituitary-adrenal axis; cortisol; AOD abstinence; chronic AODE (alcohol and other drug effects); corticotropin RH; arginine; vasopressin; adrenocorticotropic hormone; secretion; metabolic disorder; AODR (alcohol and other drug related) disorder; mood and affect disturbance; personality disorder; infection; drug therapy; literature review tress is a ubiquitous and unavoid- a wide range of critical physiological secretion occurs during both chronic able experience of daily life whether processes, the activity of cortisol must alcohol consumption and alcohol Sit arises from the external environ- be tightly controlled by the body. withdrawal. This heightened secretion ment (e.g., a job interview or traffic Cortisol secretion is regulated by rate may alter energy metabolism, accident) or from within the body (e.g., interactions among three structures: mental status, the structural integrity an infection or a panic attack). The the hypothalamus, the pituitary gland, of bone and muscle tissue, and the body has powerful mechanisms to cope and the outer layer (i.e., cortex) of each body’s ability to resist infection. In with stress. Among these mechanisms adrenal gland (see figure 1). These three addition, abstinent alcoholics exhibit is a hormone called cortisol, which is structures, collectively known as the a diminished ability of the HPA axis to produced and secreted by the adrenal hypothalamic-pituitary-adrenal (HPA) respond to stress, potentially impairing glands, located atop the kidneys (see axis, provide a regulatory network link- the body’s capacity to cope with stressors figure 1). Without cortisol a human or ing the brain with the body’s behavioral that might induce relapse to drinking. animal cannot respond appropriately to and physiological responses to stress. This article discusses the organization different types of physical or mental Alcohol consumption disrupts this and regulation of the HPA axis, disor- stress. However, because cortisol affects regulatory balance. Excessive cortisol ders associated with impaired HPA Vol. 22, No. 1, 1998 67 functioning, and the combined effects together to stimulate the release of activation (i.e., a negative feedback of long-term alcohol consumption and adrenocorticotropic hormone (ACTH). system). The hypothalamus and the HPA disturbance on health. ACTH arrives at the adrenal cortex pituitary gland are sensitive to inhibition via the bloodstream, where it stimu- by cortisol. Thus, when activation of lates the secretion of cortisol. Cortisol the stress response produces increases The HPA Axis and Stress then travels through the bloodstream, in CRH and ACTH, the resultant exerting effects on multiple organs elevation in cortisol (after a time delay) and tissues. suppresses further CRH and ACTH Organization and Regulation The HPA axis demonstrates a con- production. of the HPA Axis sistent, daily (i.e., circadian) pattern. These interactions help ensure that In humans, cortisol levels decrease the body’s stress response system does In response to stimulation from the during the late evening hours, reach- not overreact in its response to a stressor brain, the hypothalamus produces ing their lowest point during the early (Munck et al. 1984). This constant corticotropin releasing hormone (CRH) morning hours. Cortisol secretion adjustment and readjustment of hor- and/or arginine vasopressin (AVP)1 begins to increase several hours prior mone levels around a target concen- (Rivier 1996). CRH and AVP are to awakening, and peak levels occur tration has been called the “allostatic then channeled directly to the pitu- in the late morning hours. In addi- load.” Humans or animals with a itary gland situated just beneath the tion, complex short-term fluctuations high allostatic load are in a state of hypothalamus (see figure 1). Within of cortisol levels occur within the day perpetual anxious anticipation. The the pituitary, these two hormones act (Gudmundsson and Carnes 1997; chronic elevation in cortisol induced Johnson and Veldhuis 1995). by a persistent or repetitive allostatic Bryon Adinoff, M.D., is the Distinguished The HPA axis incorporates a sys- load can activate the synthesis of CRH Professor of Alcohol and Drug Abuse tem of controls that dampen its own by the brain, thereby increasing levels Research and associate professor in the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, and medical director of the Substance Abuse Team at the Dallas Hypothalamus Veterans Affairs Medical Center, VA North Texas Health Care System, Dallas, Texas. ALI IRANMANESH, M.D., is associate professor of endocrinology in the Department of Medicine, University Pituitary gland of Virginia School of Medicine, Charlottesville, Virginia, and is chief of the Endocrine Section and director of the Endocrine Laboratory, Salem VA Medical Center, Salem, Virginia. JOHANNES VELDHUIS, M.D., is a professor of endocrinology in the Depart- Adrenal gland ment of Medicine and director of the General Clinical Research Center, University of Virginia School of Medicine, Kidney Charlottesville, Virginia. LISA FISHER, PH.D., is an assistant professor in the Department of Psychiatry, University of Texas Southwestern Medical Center, and a staff psychologist at the Dallas Veterans Affairs Medical Center, VA North Texas Health Care System, Dallas, Texas. 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. 1Vasopressin is a hormone with several functions in the body, including regulating water balance. 68 Alcohol Health & Research World Disturbances of the Stress Response of anxiety and fear (McEwen 1994; metabolism, high blood pressure, major Alcohol-Related Schulkin et al. 1994). alterations in mood, impaired mental Disturbances in the functioning, and disturbed sleep. HPA Axis Excess cortisol also impairs the Disorders Associated brain’s ability to metabolize energy, with Disrupted HPA Axis which can leave the brain vulnerable Alcohol Consumption Functioning to low levels of oxygen (such as and Withdrawal following a stroke or heart attack) or A disordered HPA axis response can Investigators have explored the time cause major physiological damage. low blood sugar (i.e., hypoglycemia). course and mechanisms of alcohol- When excess cortisol is produced, Long-term damage to the hippocam- induced HPA axis activation in rodents often because of an ACTH-secreting pus—a brain structure vital to learn- (see Rivier 1996; Eskay et al. 1995). tumor in the pituitary gland (i.e., ing, memory, and the regulation of Although alcohol itself does not Cushing’s syndrome), patients may HPA axis function—appears to occur appear to exert a powerful direct stim- experience symptoms related to in chronic medical and psychiatric ulatory effect on the adrenal cortex, excess levels of the normal physiologi- illnesses associated with persistently increased rates of CRH synthesis, cal activity of cortisol (see textbox). elevated levels of cortisol (Sapolsky coupled with increased secretion of ACTH and cortisol, are generally These symptoms include increased 1996). observed in animals following long- blood sugar, bone weakness, decreased Conversely, a deficiency of cortisol resistance to infection, increased fat term alcohol administration. The can lead to low blood glucose levels effects of short- and long-term alco- and a decreased ability to convert hol consumption in humans are less lipid and protein molecules to glu- clear, although most studies suggest Physiological Effects cose. Symptoms of cortisol deficiency that chronic administration of alcohol of Cortisol include low-grade fever, easy fatigabil- increases cortisol in humans. ity, weakness, weight loss, muscle Both human and animal studies Although the physiological aches, abdominal pain, vomiting, clearly demonstrate an increase in effects of cortisol are well docu- low blood pressure, and personality HPA axis activation with elevated mented, the role of these effects changes such as irritability and restless- cortisol concentrations during alcohol in stress resistance is uncertain. ness. More severe and life-threatening withdrawal (Iranmanesh et al. 1989). Cortisol is one of several steroid consequences, such as cardiovascular In alcoholics with high daily alcohol hormones produced by the outer