Modifiers of the Stress-Alcohol Interaction

Genetics. Various inbred murine and rodent strains differ in their sensitivities to alcohol at the endocrine and behavioral levels. In the past 2 decades, with the application of selective breeding techniques, rodent models of alcoholism have been derived with high and low oral alcohol preference. Such animal models are particularly useful in the identification of genetic traits associated with the physiological and behavioral bases of alcohol drinking.

For example, results indicate that the ß-EP system of alcohol-preferring rats is hyperresponsive to alcohol. Thus, the activation of the endogenous opioid system may either enhance the reinforcing effects of low-dose alcohol or attenuate the aversive effects of high-dose alcohol and thereby affect alcohol consumption, consistent with the previously noted endorphin compensation hypothesis.

The genetic basis for susceptibility to alcohol abuse and dependence has long been accepted, and numerous studies have been conducted to determine how those with a family history of alcoholism (family history positive, FHP) might differ from those without such an inherited risk (family history negative, FHN).

There is increasing support that altered neuroendocrine responses to alcohol in the sons of alcoholic men provide a possible basis for the genetic component in the development of alcoholism. For example, nonalcoholic male offspring of alcoholic fathers (known to be at three- or fourfold higher risk for alcoholism than sons of nonalcoholics) demonstrate, in comparison to the sons of non-alcoholics, lower cortisol responses to alcohol, an impaired ACTH response to CRH, increased alcohol-induced plasma ß-EP levels, and an enhanced ACTH response to the opioid receptor antagonist, naloxone.

These findings indicate that FHP men have altered hypothalamic CRH neuronal activity. Although it is not clear how these alterations may contribute to the development of abusive patterns of alcohol use, these studies suggest that the CRH-mediated response of the HPA axis or the ß-EP system to alcohol may serve as a marker to distinguish individuals at risk for alcoholism. Interestingly, these markers do not effectively distinguish FHP women, supporting the notion that there are gender differences in the role of genetic factors in the etiology of alcoholism.

Expectancy. Adding an additional level of complexity to the determination of the effects of alcohol on the human stress response is the vast literature demonstrating that expectancies have a significant impact on the response to alcohol ingestion. It may be that many reported differences in the literature are created by the influence of cognition on reactivity to alcohol and are due to the timing of stress presentation with respect to alcohol use. Indeed, it appears that intoxication prior to stress exposure may alter the cognitive reaction to the stimulus and, as a result, the response to the stressful stimulus may be minimized.

Thus, it may be that alcohol does not merely dampen the stress response but that alcohol may also act to reduce the physiological response to a stressor by altering the appraisal of the stressful stimulus. Such a conclusion is supported by studies that find that more complex paradigms are more likely to result in alcohol stress- response dampening.

Conclusion. There is clearly a relationship between alcohol and stress, although the nature of this association is complex and not easily described. A brief look at the relevant literature demonstrates that the interaction of alcohol and stress varies with characteristics of the subject studied, the environment, the alcohol dose, the nature of the stressor imposed, and the timing of the exposure to alcohol and the stressor.

Thus, stress, alcohol, and alcoholism are interrelated, but the nature of this relationship is highly variable. The ineffectiveness of many strategies for prevention and treatment of alcohol abuse and the variation in clinical history represent a challenge and an opportunity to better understand the relationship between alcohol and stress.