Effects of stress and alcohol on subjective state in humans

BACKGROUND: There is increasing evidence that stress and hypothalamic-pituitary-adrenal axis activation interact with drugs of abuse and influence drug-taking behaviors. Both studies with laboratory animals and survey data with alcohol users suggest that acute or chronic stressful events increase alcohol intake. One mechanism for the increase in alcohol intake may be that stress alters the subjective effects produced by the drug in ways that enhance the reinforcing properties of alcohol. Therefore, in this study we determined whether an acute social stressor alters subjective responses to ethanol in humans. The stressor was a modified version of the Trier Social Stress Test, an arithmetic task that increases cortisol levels. METHODS: Twenty male volunteers participated in two laboratory sessions, in which they performed the Trier Social Stress Test on one session and no task on the other session, immediately before consuming a beverage that contained ethanol (0.8 g/kg in juice) or placebo (juice alone). Eleven subjects received ethanol on both sessions, and nine subjects received placebo on both sessions. Primary dependent measures were self-report questionnaires of mood states. Salivary levels of cortisol were obtained to confirm the effectiveness of the stress procedure. RESULTS: Stress alone produced stimulant-like subjective effects. In the group who received ethanol, stress increased sedative-like effects and decreased stimulant-like effects. CONCLUSIONS: At this relatively high dose of ethanol, stress increased sedative effects of alcohol and did not increase desire for more alcohol. It is possible that in some individuals, the increased sedative effects after stress may increase the likelihood of consuming more alcohol. The effects of stress on consumption at this, or lower, doses of alcohol remain to be determined.     

Effects of acute social stress on alcohol consumption in healthy subjects

BACKGROUND: There has been renewed interest in interactions between stress and use of drugs and alcohol. Although there is evidence that stress increases drug use in human drug users and in laboratory animals, the processes by which stress affects drug-motivated behavior are not understood. Here we examined the effects of an acute social stressor (performing a mental arithmetic task in front of an audience) on consumption of ethanol or placebo beverages in healthy social drinkers. METHODS: Thirty-seven men and women, ages 21-35, were randomly assigned to a placebo (n = 15) or ethanol group (n = 22). Subjects participated in two sessions, one with stress (Trier Social Stress Test) the other without stress. In each session, immediately after the stress or no-stress period, subjects consumed the first dose (placebo or 0.3 g/kg of ethanol for men or 0.2 g/kg for women). Then, subjects were allowed to choose up to six more beverages (0.1 g/kg each for the ethanol group or placebo beverages for the placebo group). Measures included percentage of beverage consumed, salivary cortisol level, heart rate, blood pressure, and subjective ratings of mood and drug effect. RESULTS: Subjects in both the placebo and ethanol groups consumed significantly more of their beverages after stress, compared to no stress. Stress increased anxiety, uneasiness, and produced some stimulant-like effects and, in the ethanol group, it dampened some of the acute subjective effects of ethanol. The direct physiologic and mood effects of the stress were fairly short-lived. CONCLUSIONS: It is concluded that acute stress may produce a modest increase in alcohol consumption in healthy, nonproblem social drinkers but that this increase is not directly related to the pharmacological effects of the drug. Nonpharmacological factors may include expectancies, thirst, or nonspecific facilitation of ongoing behaviors.     

An acute psychosocial stressor does not potentiate alcohol cue reactivity in non-treatment-seeking alcoholics

Background: Relapse risk factors, such as psychological stress and alcohol cues, are often encountered together. Understanding how they interact has the potential to improve alcoholism treatments. This study was conducted to examine whether an acute psychosocial stressor enhanced alcohol cue reactivity in non‐treatment‐seeking alcoholics. Methods: Seventy‐nine alcohol‐dependent individuals (39 women) randomly received either the Trier Social Stress Test or a no‐stress control condition. Stress reactivity was measured with serum adrenocorticotropic hormone and cortisol, mean arterial blood pressure, and subjective distress. Immediately following the stress manipulation, participants held and sniffed a neutral cue then their preferred alcoholic beverage. Cue reactivity was measured by 2 subjective measures of craving following each cue. Additionally, general craving was assessed with the Alcohol Urge Questionnaire at the beginning and end of the laboratory procedure. Results: The stress manipulation showed internal validity on all measures of stress reactivity. There was not a main effect of stress nor a stress × cue interaction on either cue reactivity measure. As expected, there was a main effect of cue (alcohol > neutral cue) on both measures of cue reactivity. General craving increased during the challenge, but not differently by stress group. Magnitude of stress reactivity was not associated with magnitude of cue reactivity, and all results were independent of gender. Conclusion: In this well‐controlled clinical laboratory study of non‐treatment‐seeking alcoholics, an acute psychological stressor did not make an alcohol cue a more potent urge‐inducing stimulus, and stress had no effect on general alcohol craving.     

Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings

Background: Stress, alcohol cues, and dysregulated stress responses increase alcohol craving and relapse susceptibility, but few pharmacologic agents are known to decrease stress‐ and cue‐induced alcohol craving and associated stress dysregulation in humans. Here we report findings from a preliminary efficacy study of the alpha‐1 receptor antagonist, prazosin, in modulating these relapse‐relevant factors in alcohol‐dependent individuals. Methods: Seventeen early abstinent, treatment‐seeking alcohol‐dependent individuals (12 men and 5 women) were randomly assigned to receive either placebo or 16 mg daily prazosin in a double‐blind, placebo‐controlled manner over 4 weeks. During week 4, all patients participated in a 3‐day laboratory experiment involving 5‐minute guided imagery exposure to stress, alcohol cue, and neutral‐relaxing/control conditions, 1 exposure per day, on consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, negative emotion, cardiovascular measures, and plasma hypothalamic–pituitary–adrenal (HPA; cortisol, adenocorticotropic hormone) were assessed repeatedly in each session. Results: The prazosin group (n = 9) versus the placebo group (n = 8) showed significantly lower alcohol craving, anxiety, and negative emotion following stress exposure. The placebo group also showed significantly increased stress‐ and cue‐induced alcohol craving, anxiety, negative emotion, and blood pressure (BP), as well as a blunted HPA response relative to the neutral condition, while the prazosin group showed no such increases in craving, anxiety, negative emotion, and BP, and no blunted HPA response to stress and alcohol cue exposure. Conclusions: Prazosin appears efficacious in decreasing stress‐ and cue‐induced alcohol craving and may normalize the stress dysregulation associated with early recovery from alcoholism. Further research to assess the efficacy of prazosin in reducing alcohol craving and stress‐related relapse risk is warranted.     

Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men

BACKGROUND: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. METHODS: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. RESULTS: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. CONCLUSIONS: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.     

The heritability of hypothalamus pituitary adrenal axis responses to psychosocial stress is context dependent

Individual differences in the response of the hypothalamus pituitary adrenal axis to stress are known to play an important role in health and disease risk. The origins, or determinants, of these individual differences are not well understood. To date, no study has examined the effects of context on the heritability of psychoendocrine stress responses. In the present study, 58 male twin pairs were exposed to a psychosocial stressor (Trier Social Stress Test) three times at weekly intervals, and their salivary and total cortisol, ACTH, and heart rate responses were assessed. Modest heritabilities were observed for all measures at the first stress exposure (all h2 < 0.33), but heritability estimates increased substantially with repetition of the stressor (T3: all h2 > 0.97). Concurrently, only the first but not the second and third Trier Social Stress Test exposure induced a significant increase in state anxiety (T1: P < 0.01, T2 and T3: n.s.), suggesting low heritabilities in a new, anxiety-evoking context and high heritabilities in a familiar, low-anxiety context. These findings challenge previous reports on a low heritability of markers of stimulated hypothalamus pituitary adrenal axis activity and are the first to document the relevance of context for psychoendocrine heritability estimates.     

Role of GABRA2 in moderating subjective responses to alcohol

Background: Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ‐aminobutyric acid A (GABA_A) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. Methods: One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. Results: Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence–associated allele regardless of ALDH2 genotype. Conclusions: These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.     

The fear-factor stress test: an ethical,non-invasive laboratory method that produces consistent and sustained cortisol responding in men and women

We describe a method to administer a controlled, effective stressor to humans in the laboratory. The method combines the Trier Social Stress Test (TSST) and the Cold Pressor Test into a single, believable procedure called the Fear-Factor Stress Test (FFST). In the procedure, participants imagine auditioning for the reality television show Fear Factor. They stand before a video recorder and a panel of judges while (a) delivering a motivational speech, (b) performing a verbal arithmetic task, and (c) placing one hand into a bucket of ice water for up to 2 min. We measured subjective anxiety, heart rate, and salivary cortisol in three groups of young adults (n?=?30 each, equal numbers of men and women): FFST, TSST, and Control (a placebo version of the FFST). Although the FFST and TSST groups were not distinguishable at the cortisol measure taken 5 min post-manipulation, at 35 min postmanipulation average cortisol levels in the TSST group had returned to baseline, whereas those in the FFST group continued to rise. The proportion of individual cortisol responders (≥ 2 nmol/l increase over baseline) in the TSST and FFST groups did not differ at the 5-min measure, but at the 35-min measure the FFST group contained significantly more responders. The findings indicate that the FFST induces a more robust and sustained cortisol response (which we assume is a marker of an HPA-axis response) than the TSST, and that it does so without increasing participant discomfort or incurring appreciably greater resource and time costs.     

Abstinent Alcoholics Exhibit an Exaggerated Stress Response to 2-Deoxy-D-Glucose Challenge

Chronic excessive alcohol consumption can significantly disturb the hypothalamic control of glucose metabolism; however, the mechanism and clinical significance of this disturbance are poorly understood. We used 2-deoxy-o-glucose (2-DG), which produces intracellular glucoprivation, to compare neurochemical, physiological, and behavioral responses to glucoprivic stress between alcoholics abstinent for 3 weeks and healthy volunteers. Twenty-six male alcoholics and 15 male healthy volunteers received intravenous infusions of placebo, 12.5 mg/kg, and 25.0 mg/kg of body weight of 2-DG over 30 min on three separate days, following a random-ordered, double-blind procedure. Minimal effects were obsewed following administration of the 12.5 mg/kg of body weight dose of 2-DG. Following 25.0 mg/kg, alcoholics showed both exaggerated ACTH and cortisol responses and greater increases in caloric intake when compared with controls. Although anxiety, desire to consume alcohol, plasma progesterone, and sympathetic and adrenal medullary activity all increased following 2-DG, these responses did not differ between alcoholics and controls. The present findings suggest certain specificity for the exaggerated hypothalamic and adrenocortical responses to mild glucoprivic stress in 3-week-abstinent alcoholics.     

Atomoxetine Attenuates Dextroamphetamine Effects in Humans

Background: Although preclinical studies support the contribution of the noradrenergic system activation in mediating the acute effects of amphetamines, these findings have not been followed up in clinical studies. Objectives: To examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. Methods: Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments each lasting for 4 days. On Day 4 of each treatment period, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. Results: Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of “stimulated,” “high,” and “good drug effects.” Conclusions: These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses. Scientific significance: Atomoxetine's capacity to attenuate some of the physiological and subjective responses to dextroamphetamine supports its potential use for stimulant addiction.     

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.     

Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals

BACKGROUND: Research has shown that exposure to stress/negative affect and to alcohol cues can each increase alcohol craving and relapse susceptibility in alcohol-dependent individuals. However, whether the emotional and physiological states associated with stress-induced and alcohol cue-induced craving are comparable has not been well studied. Therefore, this study examined the craving, emotional, and physiological responses to stress and to alcohol cues in treatment-engaged, 4-week abstinent, alcohol-dependent individuals using analogous stress and alcohol cue imagery methods. METHOD: Twenty treatment-seeking, alcohol-dependent participants (18 males/2 females) were exposed to a brief 5-minute guided imagery procedure that involved imagining a recent personal stressful situation, a personal alcohol cue-related situation, and a neutral-relaxing situation, 1 imagery per session presented in random order. Alcohol craving, anxiety and emotion rating scales, cardiovascular measures, and salivary cortisol were compared across the 3 conditions. RESULTS: Exposure to stress and to alcohol cues each produced significant increases in alcohol craving, anxiety, and negative emotions and decreases in positive emotions. Stress-induced alcohol craving was significantly correlated with increases in sadness, anger, and anxiety ratings, but alcohol cue-induced craving was associated with decreases in positive affect (joy and neutral relaxed state) and increases in anxiety and fear ratings. Furthermore, stress increased systolic and diastolic blood pressure responses, but significant increases in salivary cortisol were only observed in the alcohol cue condition. CONCLUSIONS: Although both stress and alcohol cues produce increases in anxiety associated with alcohol craving, each produced a dissociable psychobiological state involving subjective emotional, cardiovascular, and cortisol responses. These data could have significant implications for understanding the specific psychobiology associated with stress or alcohol cue exposure and their potential effects on alcohol relapse susceptibility.     

Hormone responses to social stress in abstinent alcohol-dependent subjects and social drinkers with no history of alcohol dependence

BACKGROUND: Previous studies have described blunted stress hormone responses after pharmacological activation of the hypothalamic-pituitary-adrenal (HPA) axis in sober alcoholics. The aim of the present study was to compare ACTH, cortisol, and prolactin responses to a psychological stressor in abstinent alcohol-dependent subjects matched to healthy control subjects. METHODS: Individuals who met DSM-IV diagnostic criteria for a history of alcohol dependence but not for other axis I disorders were included in the study (n = 18; mean duration of abstinence +/- SEM, 3.5 +/- 5.7 years). Social drinkers (n = 23) served as control subjects. The sober alcohol-dependent and control subjects were matched for demographic measures including levels of stress symptoms. All subjects underwent the Trier Social Stress Test (TSST), a laboratory-based psychological stressor. Prestress and poststress plasma ACTH, cortisol, and prolactin levels, as well as a self-report measure of anxiety (State-Trait Anxiety Inventory), were obtained. RESULTS: Nondepressed, abstinent alcoholics and control subjects did not differ with regard to age, racial composition, or baseline or poststress ratings of anxiety. Whereas ACTH and cortisol levels increased in response to the TSST, prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and control subjects. CONCLUSIONS: When matched for levels of stress, a laboratory-based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and control subjects.     

Salivary stress biomarkers of recent nicotine use and dependence

Background: Although stress plays a critical role in vulnerability to nicotine use and dependence, the stress response factors that contribute to smoking behaviors remain poorly elucidated. To minimize the confounding effects of chronic nicotine use, assessing individuals with relatively short smoking histories is critical for characterizing the neurobiological substrates associated with nicotine dependence early in the course of illness. Objectives: This pilot study examined sympathetic nervous system (alpha-amylase) and hypothalamic–pituitary–adrenal axis (cortisol, dehydroepiandrosterone) responses to the Trier Social Stress Test (TSST) in young adult smokers. Associations among objective indices of recent smoking (salivary cotinine, carbon monoxide in the breath [CO]), behavioral measures of nicotine dependence and withdrawal, and salivary biomarkers in response to the TSST were investigated. Methods: Smokers (N = 64; 28 males, 36 females) provided saliva samples at 30 min intervals for 2 h prior to the TSST and every 10 min for 1 h following the TSST. Results: Alpha-amylase responses to the TSST were positively associated with salivary cotinine levels but negatively associated with CO levels. Individuals with a lower level of nicotine dependence had increased cortisol responses to the stressor, whereas those with a higher level of nicotine dependence did not show any cortisol changes in response to the stressor. Conclusions: These findings indicate that different mechanisms may be involved at different levels of nicotine dependence severity. Recent nicotine use and lower dependence severity may be associated with increased activation of the stress response systems. In contrast, more severe levels of dependence may downregulate stress response systems.     

Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors

Background: Ethanol reduces N‐methyl‐d ‐aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine_B co‐agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine_B co‐agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine_B partial agonist, d ‐cycloserine (DCS), and ethanol in healthy human subjects. Methods: All subjects completed 4 test days under double‐blind conditions in which DCS or placebo was administered orally prior to ethanol or an ethanol‐tainted placebo drink. Two groups of healthy subjects were studied. A first group of subjects (n = 25) were pretreated orally with DCS 500 mg or placebo 4 hours prior to ethanol (0.8 g/kg, p.o. or placebo) administration. A second group of subjects (n = 20) were pretreated with DCS 1000 mg or placebo prior to ethanol administration. Outcomes included subjective and cognitive responses to the experimental interventions. Results: Predictable ethanol responses were observed in both groups of subjects, although the response to ethanol and the breath alcohol levels, but not plasma alcohol levels, were slightly but significantly lower in the group that received the higher DCS dose. DCS produced mild sedative effects that were greater for the lower than the higher dose. It also produced a mild impairment of verbal fluency without impairing attention. No statistically significant interactions between ethanol and DCS emerged in analyses. However, the combination of ethanol and DCS produced significantly greater impairment than both ethanol or DCS administered alone on a test of verbal fluency and aspects of memory function. Implications: DCS and ethanol both produced sedative and cognitive effects, consistent with their ability to reduce NMDA receptor function. However, the absence of interactive effects observed in this study raises questions about the clinical significance of the glycine_B site as a target for ethanol in the brain at levels of ethanol intoxication associated with social drinking. However, it should be noted that this conclusion is limited to the dependent measures evaluated and the doses of ethanol and DCS studied.     

Anticipated Biphasic Effects of Alcohol Vary with Risk for Alcoholism: A Preliminary Report

Twenty-five sons of alcoholic fathers and 114 sons of nonalcoholic fathers reported the stimulant and sedative effects they expected alcohol would produce on both the ascending and descending limbs of the blood alcohol curve. High-risk subjects anticipated more stimulation on the ascending limb, and more sedation on the descending limb than low-risk subjects. These results are comparable to some studies of subjective responses to alcohol in high- and low-risk men, and to previous work on risk and anticipated effects. These expectancies may contribute to risk-related differences in responses to alcohol, as well as the development of problem drinking.     

Family history of alcoholism and response to amphetamine: sex differences in the effect of risk

BACKGROUND: Individuals at risk for alcoholism exhibit an enhanced stimulant response to alcohol. It is not known whether individuals at risk also exhibit a heightened sensitivity to other drugs with stimulant properties. METHODS: Healthy young men and women each received, in separate sessions, placebo and 10 mg of d-amphetamine in counterbalanced order. Stimulant and sedative subjective effects were recorded before and three times after capsule administration using the Biphasic Alcohol Effects Scale. The sample comprised 19 family-history-positive (FHP; 58% women) and 53 family-history-negative (FHN; 51% women) participants. RESULTS: As compared with placebo, amphetamine increased ratings of stimulation in the sample as a whole. In addition, the ratings revealed an enhanced, as well as a protracted, stimulant response to amphetamine among FHP men, as compared with FHN men: for FHP men, ratings of stimulation made 3 and 6 hr after amphetamine administration were greater than baseline ratings. Moreover, in FHP men, the effect of amphetamine, as compared with placebo, was most evident 6 hr after capsule administration. In contrast, despite a dose x hour interaction in FHN men, post hoc comparisons revealed no differences between the baseline and any of the postamphetamine measurements or between amphetamine and placebo ratings at any of the time points. Among women, the drug effect did not differentiate the family-history groups. CONCLUSIONS: Consistent with previous research on alcohol, high-risk men exhibited a heightened stimulant response to amphetamine. Thus, for men, sensitivity to the stimulant properties of drugs may be an endophenotype for alcoholism. Whereas the present results suggest that women at risk do not exhibit an enhanced stimulant response to amphetamine, further study is needed, including evaluation at various points in the menstrual cycle.     

Stress,Motivation, and the Gut–Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder

Since its discovery, the gut hormone, ghrelin, has been implicated in diverse functional roles in the central nervous system. Central and peripheral interactions between ghrelin and other hormones, including the stress‐response hormone cortisol, govern complex behavioral responses to external cues and internal states. By acting at ventral tegmental area dopaminergic projections and other areas involved in reward processing, ghrelin can induce both general and directed motivation for rewards, including craving for alcohol and other alcohol‐seeking behaviors. Stress‐induced increases in cortisol seem to increase ghrelin in the periphery, suggesting a pathway by which ghrelin influences how stressful life events trigger motivation for rewards. However, in some states, ghrelin may be protective against the anxiogenic effects of stressors. This critical review brings together a dynamic and growing literature, that is, at times inconsistent, on the relationships between ghrelin, central reward‐motivation pathways, and central and peripheral stress responses, with a special focus on its emerging role in the context of alcohol use disorder.     

Subjective Response to Alcohol: A Critical Review of the Literature

Background: Subjective response to alcohol (SR), which reflects individual differences in sensitivity to the pharmacological effects of alcohol, may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders (AUDs). SR predicts alcohol use and problems and has been found to differ by a range of established risk factors for the development of AUDs (e.g., family history of alcoholism). The exact pattern of SR associated with increased risk for alcohol problems, however, remains unclear. The Low Level of Response Model (LLR) suggests that high‐risk individuals experience decreased sensitivity to the full range of alcohol effects, while the Differentiator Model (DM) asserts that high risks status is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to negative effects. Aims: The current paper (1) reviews two prominent models of subjective response, (2) reviews extant laboratory‐based research on subjective response, (3) highlights remaining gaps in our understanding and assessment of subjective response, and (4) encourages collaborative efforts to address these methodological and conceptual concerns. Methods: This paper reviews studies which employed placebo‐controlled and non‐placebo‐controlled alcohol challenge paradigms to assess a range of alcohol effects including impairment, stimulation, and sedation. Results: The research literature provides at least partial support for both the LLR and DM models. High‐risk individuals have been shown to have a reduced response to alcohol with respect to sedative or impairing effects, particularly on the descending limb of the blood alcohol curve (BAC). There is also evidence that ascending limb stimulant effects are more pronounced or operate differently for high‐risk individuals. Discussion: Despite commendable advances in SR research, important questions remain unanswered. Inconsistent results across studies may be attributable to a combination of an inadequate understanding of the underlying construct and methodological differences across studies (e.g., number and timing of assessments across the BAC, inclusion of a placebo condition). With respect to the underlying construct, existing measures fail to adequately distinguish between cognitive/behavioral impairment and sedation, aspects of which may be perceived positively (e.g., anxiolysis) due to their ability to act as negative reinforcers. Conclusions: Addressing the concerns raised by the current review will be integral to making meaningful scientific progress in the field of subjective response.     

The subjective, rather than the disinhibiting, effects of alcohol are related to binge drinking

Background: Evidence suggests that alcohol‐related problems are associated with impulsivity and disinhibited behavior. Less certain is whether disinhibited behavior is due to an impulsive disposition or alcohol’s ability to disinhibit some people more than others. There are a range of disinhibited behaviors associated with alcohol, including excessive alcohol consumption, bingeing. The study tested whether nondependent alcohol bingers showed more disinhibition after placebo and/or alcohol relative to nonbingers and whether this was related to enhanced motivation to drink following a priming dose of alcohol. Methods: Twenty participants (10 bingers) attended the laboratory twice. Baseline measures included impulsivity, alcohol‐related cognitions, alcohol urge, and mood. Participants were preloaded with alcohol (male: 0.6 g/kg, female: 0.5 g/kg) and placebo (counterbalanced). After a 20‐minute rest, participants completed 2 impulsivity tasks (Two Choice & Time Estimation) separated by second urge and mood ratings. Results: Bingers did not show greater impulsivity characteristics but were more concerned about their drinking (p = 0.02) and ability to control drinking (p = 0.04). A priming effect was found: alcohol urge increased after alcohol but not placebo (p = 0.006). Bingers reported greater tolerance to the sedative (p = 0.05) and lightheaded (p = 0.04) effects of alcohol, relative to nonbingers. Binge status was not associated with impulsivity task performance, while preload type (alcohol/placebo) supported only marginal associations. Conclusions: Risk of binge drinking in nondependent individuals is not strongly affected by impulsive personality characteristics or alcohol’s ability to induce behavioral disinhibition. However, alcohol did lead to a priming effect and bingers were more tolerant to the sedative and lightheaded effects of alcohol relative to placebo. Risk of binge drinking is associated with the subjective effects of a priming dose of alcohol.