Alcohol, Aging and Stress : Part 2

by National Institute of Health

(Page 2 of 5)

Because the majority of alcoholics do not develop pseudo-Cushing's syndrome, most people probably experience some adaptation or tolerance to the HPA axis' response to alcohol. This adaptation, however, may negatively affect the ability of the HPA axis and other physiological systems to maintain their normal functions. The cost of physiological adaptation to alcohol becomes evident when alcohol is suddenly withheld and the drinker experiences withdrawal symptoms (anxiety, increased heart rate, and tremors).

A few studies have shown that alcohol withdrawal also leads to excessive activation of the HPA axis. Thus, alcohol consumption, particularly in alcoholics, can interfere with normal HPA axis functioning during acute intoxication, chronic alcohol consumption (when tolerance development can alter HPA axis activity), and withdrawal after a bout of drinking. Moreover, the normal functioning of the HPA axis and its response to other stimuli appear to be compromised in alcoholics. In some studies various stimuli (surgical procedures or administration of the hormones insulin and ACTH [adrenocorticotropic hormone]) resulted in lower-than-expected HPA axis responses.

Glucocorticoid Contributions to the Rewarding Effects of Alcohol

The interaction between alcohol and the HPA axis may be bidirectional - that is, not only does alcohol consumption stimulate cortisol secretion, but elevated cortisol levels may increase drinking by magnifying its rewarding effects. Evidence for the latter relationship between alcohol and the HPA axis derives from animal studies in which researchers experimentally manipulated corticosterone levels. In those studies, rats that produced no corticosterone because their adrenal glands had been surgically removed (the rats had been adrenalectomized) exhibited a dramatic reduction in voluntary alcohol intake. Treatment of the adrenalectomized rats with corticosterone restored their alcohol intake to levels comparable to, and sometimes higher than, the levels before the surgery. Similarly, rats with functional adrenal glands that were treated with a chemical preventing corticosterone production also exhibited decreased alcohol consumption. Finally, the injection of corticosterone directly into the brains of normal rats that displayed a moderate preference for alcohol resulted in enhanced alcohol intake in those animals.

Researchers have speculated that corticosterone may increase an individual's alcohol consumption by enhancing alcohol's rewarding effects (feelings of euphoria). The mechanism underlying this process may involve corticosteroneinduced alterations in the levels of the brain chemical (neurotransmitter) dopamine in the brain region called the nucleus accumbens.4 In studies of the effects of cocaine or morphine exposure, corticosterone increased dopamine release in the nucleus accumbens and that brain response appeared to be critical for the euphoria-inducing effects of the cocaine or morphine. Similarly, high glucocorticoid levels present in the brain during times of stress may facilitate alcohol's rewarding properties, providing a potential explanation for survey results indicating that stress may contribute to heavy alcohol use in humans. This aspect of the stress-alcohol interaction warrants further systematic investigation in humans.

Another variable that plays a role in the HPA axis' response to both stress and alcohol's effects is the aging process. Aging is associated with gradual, but often dramatic, changes over time in almost every physiological system in the human body. Combined, these changes result in decreased efficiency and resiliency of physiological function. The aging process is highly variable, however, with large individual differences in the overall rate of aging as well as in the specific patterns of age-related manifestations.

As described in detail in the sidebar entitled "Chronic Alcohol Consumption and Aging", considerable evidence suggests that a twoway interaction exists between alcohol abuse and aging. On the one hand, aging may alter a person's physiological and psychological responses to alcohol. On the other hand, chronic alcohol use may alter the aging process, as indicated by several studies that found evidence for premature or exaggerated aging in chronic heavy drinkers.

Stress Hormone Activity and Aging Just as a two-way interaction appears to exist between alcohol and aging - that is, 1. aging can modify the body's response to alcohol, and 2. chronic alcohol exposure can modify the aging process - an analogous two-way interaction also appears to exist between stress and aging. This two-way interaction is probably mediated by the HPA axis. Thus, elderly people appear to have an impaired resiliency of the HPA axis response to the acute effects of stress. In addition, chronic stress may accelerate the aging process by causing overactivity of the HPA axis.

Age Differences in HPA Axis Function

Animal studies have demonstrated that HPA axis function changes as the animal enters the last quarter of its normal life span. Several studies have found that although rats of all ages experience a similar increase in HPA activity in response to stress, aged rats, compared with younger ones, show increased HPA activity in the absence of stress (increased basal activity) and a slower return to basal activity after a stressinduced increase in activity. Consequently, the bodies of aged rats are exposed to a substantially greater overall amount of glucocorticoid hormones than are the bodies of younger rats.

Studies in which rats were repeatedly exposed to the same stressful event also have found age-related changes in HPA axis function. In general, the HPA axis response decreases (habituation occurs) in response to repeated stress, similar to the tolerance development in response to repeated alcohol exposure. This habituation likely minimizes the amount of glucocorticoids to which the body is exposed. Aged rats, however, experience a slower rate of stress habituation than do younger rats.

When analyzed together, the observed age-related changes in HPA activity suggest that the resiliency of the HPA axis in response to acute stress, as well as its ability to adapt to chronic stress, is impaired in older animals. Researchers have not yet identified the mechanism underlying this impaired HPA axis resiliency. One potential mechanism might involve changes in the levels of glucocorticoid receptors that contribute to the negative feedback regulation of glucocorticoid secretion, because aged rats tend to show reduced numbers of those receptors in certain brain regions (the hypothalamus and the hippocampus).

Researchers have not yet determined if impaired HPA axis resiliency also occurs during human aging. Older people, even those in their seventies, generally do not exhibit elevated basal cortisol levels. However, researchers have not examined in elderly people the ability of the HPA axis to return to basal levels after acute stress or to habituate after repeated stress.

Some evidence indicates that elderly people may be less sensitive than younger people with respect to the negative feedback control of cortisol levels. For example, older people who received a dose of the potent synthetic glucocorticoid dexamethasone exhibited a blunted negative feedback response and thus were exposed to higher overall glucocorticoid levels than were younger people undergoing the same procedure. Furthermore, such an impaired response to dexamethasone occurs more consistently in older people suffering from major depression than in younger people with a similar degree of depression. Finally, older people suffering from Alzheimer's disease or other forms of dementia also demonstrate a relatively high incidence of a blunted dexamethasone response.

A series of studies have shown that dexamethasone exerts its primary negative feedback effects on the HPA axis by directly suppressing ACTH release from the pituitary. To date, researchers do not know the extent to which an impaired response to dexamethasone reflects a localized impairment in pituitary activity or changes in negative feedback sensitivity originating in other brain regions that affect pituitary function, such as the hypothalamus. On the other hand, cortisol is known to produce negative feedback effects on HPA axis activity by acting at the level of certain brain structures, such as the hypothalamus and hippocampus. A recent study showed impaired negative feedback sensitivity among older people to cortisol, suggesting that an age-related impaired sensitivity to glucocorticoid negative feedback is attributable to changes in the brain. Because negative feedback is an important mechanism that allows an organism to both recover from stress and turn off its HPA axis response to stress, impaired glucocorticoid negative feedback likely results in prolonged elevation of cortisol levels during stressful circumstances.

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