This study aimed to investigate interactions between acute stress and low doses of alcohol in healthy male social drinkers. We examined stress-alcohol interactions in relation to the time between the stressor and alcohol administration, and in relation to individual differences in subjective responses to alcohol. There were several interesting findings. First, when all subjects were considered together, acute stress did not influence subjective responses to alcohol, whether it was administered immediately after stress or 30 min later. However, when subjects were separated into those who reported predominantly positive stimulant-like or predominantly negative sedative responses to alcohol (in the non-stressful control condition), stress differentially influenced the subjective effects of alcohol in each group. Among participants who reported mainly stimulant-like effects from alcohol on the non-stress session, stress blunted ratings of stimulation, and wanting more drug, and increased sedation, which was in contrast to our hypothesis. Conversely, among participants who did not report stimulation from alcohol, stress decreased alcohol-induced sedation and increased ratings of “want more drug”. We also found that alcohol administered immediately after stress blocked the stress-induced increase in cortisol, yet prolonged negative subjective responses. The latter finding may have implications for the interpretation of the stress-dampening effect of alcohol. Overall, the findings provide evidence of bi-directional interactions between alcohol and stress, which could influence drinking under stressful conditions.
This study is among the first to investigate stress-drug interactions using alcohol delivered intravenously. Although the intravenous alcohol administration procedure is usually employed to maintain steady breath alcohol concentrations over a prolonged period, the alcohol “clamp” (O'Connor et al., 2000
), in this study we administered the drug in a single, relatively brief dose. We used a model-based algorithm of alcohol distribution and elimination to calculate the infusion rates that would yield the same target concentration of BrAC within a set interval in all subjects. Then, the pumps were turned off once the prescribed peak BrAC was achieved, allowing BrAC levels to decline immediately. Our rationale for i.v, alcohol administration was fourfold. First, we wanted to be able to control when peak BrACs were achieved in relation to the stress response (e.g., when responses were near maximal immediately after the task, or during recovery approximately 30min later). Second, intravenous infusion avoids the delay of approximately 30min to peak BrACs when alcohol is ingested orally, thus we were able to administer alcohol immediately after the stressor and achieve peak BrAC in 5 minutes to coincide with near maximal stress responses. Alcohol administered orally before the stress confounds the effects of alcohol on perception of the stress task from its effect on the response to the stress task, and alcohol administered orally after stress might miss the peak time of stress effects. Third, the method avoided the substantial inter-individual variation in absorption kinetics of alcohol when it is administered orally. Finally, we wanted to blind participants to the drug that was being administered in order to minimize expectancy effects. Responses to the questionnaire given at the end of each session indicated that blinding was moderately effective; only 12 of 25 subjects correctly identified the drug as alcohol during one of the sessions, and only 36% of all drug identifications were correct.
There are both commonalities and differences in the effects of alcohol administered by the oral and intravenous route. We and others (O'Connor et al., 1998
; Zoethout et al., 2009
) have found that the subjective effects of alcohol are very similar whether it is administered orally or intravenously. However, the clearance kinetics of alcohol after short high rate intravenous infusions differ from the clearance after oral administration. In our study, there was a rapid drop in BrAC immediately after the infusion was terminated as arterial, venous and body water alcohol concentrations equilibrated, which was followed by a longer pseudolinear decline at the same rate as that after oral administration. Despite the differences in kinetics, however, the subjective responses in this study were similar to those reported after oral administration paradigms (O'Connor et al., 1998
; Zoethout et al., 2009
). Another difference between the administration procedure used here and oral administration is that complete post-hepatic administration of the alcohol dose (approximately 2 standard drinks) was achieved in 5min, whereas after oral administration only approximately 10% of participants completely absorb an equivalent dose of alcohol (Ramchandani et al., 2009
). There is little evidence that this difference in speed of onset influenced the subjective or physiological responses to the drug. Thus, we believe that the intravenous route used was the most appropriate and controlled way to address the question under study.
An important finding in this study was that stress attenuated the stimulant-like effects and increased the sedative effects of alcohol among participants who exhibited stimulant-like responses to alcohol in the control condition. While these findings are in contrast to our original hypotheses, they are in line with two previous studies (de Wit et al., 2003
; Soderpalm and de Wit, 2002
) which reported that acute stress blunted the positive stimulant effects and increased the negative sedative effects of orally administered alcohol. Stress also decreased ratings of “want more drug” among stimulant responders, which is in accordance with evidence that stimulant-like effects of alcohol are positively related to alcohol consumption and liking. It is not clear how the finding that stress dampened the stimulant effects of alcohol explains stress-induced alcohol drinking. Possibly, people may drink more alcohol to overcome the attenuated effect. Alternatively, they may drink to reduce unpleasant feelings of stress or simply for the purposes of “pleasant” sedation. By contrast, among participants who did not report pleasant stimulant-like responses to alcohol during the non-stressful condition, stress attenuated the negative sedative effects of alcohol and increased ratings of want more. Thus, these individuals may experience less negative subjective effects from alcohol, and so may consume more during stress. Although this result is consistent with the expected increase in alcohol drinking after stress, it was only reported in participants who normally experience relatively negative sedative effects of alcohol. These findings suggest that stress differentially influences subjective responses to alcohol depending upon whether individuals usually experience predominantly stimulant effects of alcohol or not under normal conditions and therefore, stress-induced changes in alcohol drinking may be mediated differently among subsets of drinkers.
Another important finding in this study was that administration of alcohol immediately after stress blocked the expected increase in cortisol after stress. Previously others have shown that alcohol administered prior to stress exposure blunts ACTH and cortisol responses to stress (Dai et al., 2002
; Zimmerman et al., 2004
), but in those studies, alcohol may have affected the perception of the stressful situation, effectively reducing its strength. Here, we extend these findings to show that alcohol can inhibit the cortisol stress responses even if it is administered after exposure to the stressful stimulus. It has been proposed that alcohol inhibits stress-induced activation of the hypothalamic pituitary adrenal (HPA) axis. Several mechanisms have been proposed including actions upon excitatory and inhibitory afferents to corticotrophic releasing hormone (CRH) containing neurons of the paraventricular nucleus (PVN) (De Waele et al., 1992
; Gianoulakis 1990
; Wand et al., 1998
), actions upon GABA receptors expressed by CRH containing neurons of the PVN (Jessop et al., 1999
) or by inhibiting vasopressin which is co-released with CRH and which synergizes to enhance adrenocorticotrophic hormone (ACTH) release (Antoni, 1986
; Watabe et al., 1988
). However, our results suggest that the inhibitory effects of alcohol may be mediated downstream of the hypothalamus since alcohol was administered after stressor exposure and presumably after the hypothalamic CRH-containing neurons were stimulated. Indeed, previously it was shown that alcohol blunted ACTH response to exogenous CRH but not cortisol response to exogenous ACTH (Waltman et al., 1993
). Limitations of this study include that we did not collect blood samples for ACTH analysis, which would have aided in the interpretation of the effects of alcohol upon the HPA axis, and that we obtained a single cortisol measurement before the tasks, which provides only an approximate indicator of baseline levels. Nevertheless, our results are in line with earlier findings which suggest alcohol may decrease responsivity of pituitary ACTH-containing neurones to CRH.
Paradoxically, although alcohol administered after a stressor dampened cortisol responses, it prolonged negative subjective responses. This is inconsistent with Conger's stress-dampening theory of alcohol consumption (1956
) but is in agreement with studies demonstrating that alcohol use can actually increase stress (Pohorecky, 1991
). The body's physiological response to an acute stressor is designed to counteract the threat and to minimise perturbations by restoring homeostasis. Therefore, it may follow that if the body's normal physiological response to stress is disrupted e.g., by alcohol, then other responses i.e., psychological, may be similarly disrupted. In effect, although alcohol dampens cortisol responses to acute stress, it interrupts the body's ability to cope effectively and efficiently with a stressor thus increasing overall subjective stress levels. Previously, others reported that alcohol dampened subjective emotional responses in anticipation of a stressor (Conrod et al., 1998
; Finn et al., 1990
), however it is not clear whether this effect was due to the influence of alcohol upon perception of the stressor (Sayette, 1993
). Thus, here we demonstrate that a low dose of alcohol administered after a stressor significantly alters physiological and psychological stress responses among healthy men.
These results also have implications for studies of alcohol effects upon the HPA axis (e.g., Richardson et al., 2008
). Interestingly, high doses of alcohol (at least twice as large as that administered in the present study) have been shown to stimulate the HPA axis causing ACTH and cortisol release (McCaul et al., 2001
; Inder et al., 1995
; Reddy and Sarkar, 1993
; Rivier, 1996
; Rivier and Vle, 1988
; Silveri and Spear 2004
). These increases are thought to result from actions of alcohol upon hypothalamic paraventricular CRH neurons or their afferents (Ogilvie et al., 1998
; Rivier and Lee, 1996
) and may be mediated by local metabolism of alcohol to acetaldehyde (Cannizzaro et al., 2010
). In this study, we demonstrate that alcohol can inhibit HPA axis activity and glucocorticoid release after it has been activated by an external stimulus. Thus, as suggested by previous studies (Waltman et al., 1993
), it appears that the effects of alcohol upon HPA axis activity and glucocorticoid release i.e., stimulation or inhibition, appear to depend upon the current level of activation. Additionally, interactions between alcohol and the HPA axis may be altered with prolonged activation of the HPA system i.e., with chronic stress.
Together, the findings of this study indicate that there are bi-directional relationships between alcohol and stress. Alcohol influences responses to stress, and stress changes reactions to alcohol, and it does so differently across individuals. Considering the complex nature of these interactions, it is perhaps not surprising that it has been difficult to demonstrate consistent effects of stress upon alcohol drinking in the laboratory. Future studies may seek to investigate stress-alcohol interactions in specific, targeted subsets of drinkers or using paradigms specifically designed to measure motivational aspects of stress-alcohol interactions.