Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism

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Summary

Dysfunction of the hypothalamic–pituitary–adrenal (HPA)-axis has been observed in chronic alcoholics and in non-alcoholic sons of alcoholic parents, while genetic and environmental factors, such as stress, may play a significant role in the development of alcoholism. The present study was designed to investigate the response of the HPA-axis to alcohol and stress as a function of family history of alcoholism and chronic alcohol abuse.

We determined changes in plasma adrenal corticotrophin (ACTH) and cortisol concentrations in response to a placebo or an alcohol (0.50 g ethanol/kg body wt) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, four groups of healthy male individuals, low risk with no alcohol-dependence diagnosis (LRNAD), high risk with no alcohol-dependence diagnosis (HRNAD), low-risk alcohol dependent (LRAD) and high-risk alcohol dependent (HRAD), participated in the four experimental sessions given in random order.

Basal plasma ACTH levels of LRNAD participants were higher from those of the other three groups of participants. Basal plasma cortisol levels of HRAD participants were higher from those of LRNAD and HRNAD but not of LRAD participants. The stress-induced increases of plasma ACTH and cortisol concentrations were more pronounced in LRNAD participants. The alcohol drink prevented the stress-induced increases in plasma ACTH and cortisol of all groups of participants. The self-ratings of anxiety were attenuated in LRNAD and LRAD participants in the alcohol only session and in HRNAD and HRAD participants in the alcohol plus stress session.

In conclusion, there are differences in the activity of the HPA-axis as a function of family history and alcohol dependence, while the effect of an alcohol drink on the self-rating of anxiety may be influenced by both family history and stress.

Introduction

In both human and experimental animals the vulnerability for heavy alcohol consumption is influenced by genetic factors, with children of alcoholic parents having a higher risk of becoming alcoholics, than children of non-alcoholic parents (Cloninger et al., 1981; Goodwin, 1985; Hesselbrock, 1995; Light et al., 1996; Nurnberger et al., 2004). In addition, environmental factors, such as stress, have been associated with heavy drinking (Linsky et al., 1985; San Jose et al., 2000; King et al., 2003; Dawson et al., 2005), with job-related and legal types of stress and an income below the poverty level having the stronger association with increased frequency of heavy drinking (Dawson et al., 2005).

Among the neuroendocrine systems greatly affected by stress is the hypothalamic–pituitary–adrenal (HPA) axis. The HPA-axis response to stress is controlled by complex interactions of a number of neurotransmitter systems designed to help the individual cope with the stressful situation (Tsigos and Chrousos, 1995, Tsigos and Chrousos, 2002). A normal HPA-axis response to stress is characterized by a fast increase of corticotrophin-releasing hormone (CRH), adrenal corticotrophin (ACTH) and cortisol followed by an efficient return to pre-stress levels upon termination of the stressful challenge (de Kloet, 2004). However, either greatly attenuated or greatly enhanced hormonal responses to stress are not healthy and may be associated with psychiatric and metabolic disorders (McEwen, 1998). Indeed, a number of conditions have been reported to influence the response of the HPA-axis to stress, among which are psychological disorders such as anxiety (Jezova et al., 2004; Yehuda et al., 2004; Munro et al., 2005), depression (Carroll, 1982; Holsboer et al., 1987; Heim et al., 2004; Young et al., 2004) and family history of alcoholism (Waltman et al., 1994; Dai et al., 2002; Zimmermann et al., 2004).

The mechanisms underlying the relationship between stress and alcohol consumption are not clear. Conger (1956) proposed the tension reduction hypothesis suggesting that alcohol consumption relieves anxiety and thus may help an individual to cope with stress. However, inconsistent results have been reported with alcohol either reducing or producing anxiety (Cappell and Herman, 1972; Hodgson et al., 1979; Cappell and Greely, 1987; Pohorecky, 1991) depending on a number of factors among which are the dose of alcohol (Klatsky et al., 1977; De Turck and Vogel, 1982; Kelbaek et al., 1985), prior exposure to alcohol (Ireland et al., 1984; Marmot, 1984), and the subjective state of the individual at the time of testing (Pohorecky, 1981, Pohorecky, 1991). One biological system influenced by both alcohol and stress is the HPA-axis. The effect of stress on the activity of the HPA-axis is clear and well defined. Stress increases the HPA-axis activity (McEwen, 1998; Tsigos and Chrousos, 2002; De Kloet, 2004). The effect of alcohol on the activity of the HPA-axis is not as clear and may depend on previous alcohol exposure (Rivier and Vale, 1988; Thiagarajan et al., 1989; Rasmussen et al., 1998), dose of alcohol (Leppaluoto et al., 1975; Schuckit et al., 1987, Schuckit et al., 1988; Lukas and Mendelson, 1988; Waltman et al., 1993; Dai et al., 2002) and family history of alcoholism (Schuckit et al., 1987, Schuckit et al., 1988).

A number of studies have shown impairment in the activity of the HPA-axis of alcohol-dependent individuals. Indeed, a blunted HPA-axis response to various stressors by alcohol- and alcohol plus stimulant- (cocaine and amphetamine) dependent individuals (Lovallo et al., 2000) as well as by short- and long-term abstinent alcoholics (Adinoff et al., 1990; Errico et al., 1993, Errico et al., 2002; Costa et al., 1996) has been reported, suggesting a persistent dysfunction of the HPA-axis in alcohol-dependent individuals. On the other hand, a study using individuals without depression or family history of alcoholism and matched for various demographic characteristics and levels of stress and anxiety, reported similar responses to stress between abstinent alcohol-dependent individuals and social drinkers indicating the absence of persistent dysfunction of the HPA-axis of abstinent alcoholics (Munro et al., 2005). Most published reports compare the activity of the HPA-axis of abstinent alcohol-dependent participants with that of participants with no alcohol-dependence diagnosis. However, chronic heavy drinking may alter the function of the HPA-axis of non-abstinent alcohol-dependent individuals. Comparison of the responses to alcohol and stress by the HPA-axis of non-abstinent alcohol-dependent individuals to those of socially drinking individuals but with no alcohol-dependence diagnosis may provide important information on the alcohol–stress interactions and their impact on heavy drinking.

Since stress is one of the environmental factors associated with heavy drinking, inherited differences in the HPA-axis response to stress may exist and may influence an individuals’ ability to cope with stress and vulnerability to heavy drinking. Previous studies demonstrated a dysfunction of the HPA-axis in sons of alcoholics, predating the development of alcohol dependence, while ingestion of low amounts of alcohol prior to the stress task prevented the HPA-axis response to stress in individuals with no alcohol-dependence diagnosis, with and without a family history of alcoholism (Dai et al., 2002). Thus, investigations on the effect of alcohol on the HPA-axis responses to stress in individuals with and without an alcohol-dependence diagnosis, as well as with and without a family history of alcoholism, may help us to understand better the relationship between stress, family history of alcoholism and heavy drinking.

The present study was designed to investigate the hypothesis that the activity of the HPA-axis under basal conditions and in response to stress will be lower in alcohol-dependent individuals with and without a family history of alcoholism, than in socially drinking individuals with no alcohol-dependence diagnosis from families with and without a history of alcoholism. In addition, the hypothesis that ingestion of low amounts of alcohol prior to the performance of the stress task will prevent the HPA-axis response to stress of socially drinking individuals with no alcohol-dependence diagnosis, but not of alcohol-dependent individuals, regardless of their family history of alcoholism, was investigated.

Section snippets

Participant recruitment and selection

Participants were recruited from the Montreal area through advertisements placed in local newspapers. The investigations were approved by the Research Ethics Board of the Douglas Hospital for human studies and were conducted in accordance with the guidelines of the Declaration of Helsinki. A written consent was obtained from all participants following explanation of the research procedures. Participants could withdraw from the study at any time. All participants were males between 25 and 40

Description of the participants

The major characteristics of the participants of each group are shown on Table 1. Compared to LRNAD and HRNAD groups, participants in the LRAD and HRAD groups were older, had less years of education, higher MAST scores, more drinking days per month, more drinks per drinking day, higher activity of the enzyme γ-glutamyltransferase (GGT) and more subjects with antisocial personality disorder and cigarette smoking. Furthermore, compared to LRAD participants, HRAD abused alcohol for a longer period

Discussion

The present study compared the activity of the HPA-axis under basal conditions and in response to a mental stress task of competitive nature in participants with and without a family history of alcoholism and alcohol dependence. In agreement with previous studies (Dai et al., 2002) HRNAD participants presented lower basal plasma ACTH and similar basal plasma cortisol levels to those of LRNAD participants, suggesting a dysfunction of the HPA-axis in the sons of alcoholics prior to the

Acknowledgements

The authors wish to thank Dr. Jose A. Correa from the McGill University Statistical Consulting Service for the performance of the statistical analysis, and the nursing staff of the Clinical Research Unit of Douglas Hospital for their expert assistance. This research was supported by the Canadian Institutes of Health Research.

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