Physiological Reactivity to Alcohol Cues and the Awareness of an Alcohol Effect in a Double-Blind Placebo Design*

Skin conductance level (SCL) was recorded during the presentation of a beer drink in 16 alcoholic patients. The instructions to subjects stated that the ‘beer’ that was to be consumed‘may or may not contain alcohol. ‘Following consumption of either real beer or placebo (non-alcoholic malt beverage) the subjects were asked if they thought they had just consumed an alcoholic drink. SCL increases to the presentation of beer stimuli prior to consumption were highest among alcoholics who perceived the drink as ‘real beer’ following consumption. Perception of the drink as‘real bee' was not related to receiving real beer. The data suggest that autonomic reactivity to alcohol-related cues can facilitate and/or interact with the expectations surrounding alcohol consumption in alcohol dependent individuals.     

Neuroendocrine, Psychophysiological and Subjective Reactivity to an Alcohol Placebo in Male Alcoholic Patients

Alteration in neuroendocrine activity associated with the regulation of energy metabolism and food intake may play a role in characterizing the alcohol dependent state. Alcoholics, when compared to controls, demonstrated significantly larger and more rapid glucose and insulin responses following the consumption of a placebo beer, which they believed contained alcohol. The existence of significant correlations between peak neuroendocrine responses and desire to drink, anxiety, as well as psychophysiological responses in alcoholics suggests the potential multivariate nature of the biological/behavioral state associated with alcohol dependence.     

Tension Reduction and the Effects of Prolonged Alcohol Consumption

It has been argued that the phenomenon of alcoholics experiencing mood deterioration during a heavy drinking bout discredits the Tension Reduction Hypothesis of alcohol consumption [6]. An experiment is described which sought to illustrate two ways in which this phenomenon and the hypothesis are compatible. Nine male alcoholics consumed 6gm of alcohol per kg bodyweight in 16 equal doses over two days. Ratings of mood and related physiological indices were used. In the long-term the physiological measures were elevated on the second drinking day and yet individual doses of alcohol lowered these throughout. Severely alcohol dependent subjects showed corresponding effects for subjective ratings ie long-term mood deterioration with short-term improvement. All subjects expected continuing to drink to be reinforcing relative to stopping. Thus alcohol may retain tension-reducing properties, and alcoholics may expect these, even if affective state was worsened overall during a drinking bout.     

Psychophysiological Effects of Alcohol-related Stimuli: II. Enhancement with Alcohol Availability

This laboratory study examined methods of enhancing physiological and subjective responses of alcoholics to naturalistic alcohol-related stimuli by repeated exposures to a high-dose alcohol drink. Individual subjects participated in five successive daily sessions consisting of randomized-block presentations of gustatory and visual presentation of alcohol, pepper juice (as a control for stimulus taste intensity), or water stimuli. Following the stimulus trial series, all subjects ingested 1.5 oz of alcohol in a shot glass. Twelve subjects next received a 1.7 g/kg alcohol drink ("high dose alcohol group") on Days 1-4 and placebo on Day 5, and 12 subjects received a placebo drink on all study Days (1-5) ("placebo drink group"). On Day 1, alcohol stimuli generally elicited larger heart rate and skin conductance increases and skin temperature decreases than water or pepper juice stimuli. Alcohol stimuli also elicited greater subjective responses than either pepper juice or water. Alcohol availability within the taste trial markedly increased physiological and subjective reactivity to alcohol-related stimuli, perhaps due to the closer approximation to natural drinking behavior. A comparison with previous data from this laboratory suggests that prestudy deprivation from alcohol, instructions to expect alcohol, a conductive drink setting, and the opportunity to drink alcohol within the session may enhance reactivity to alcohol stimuli in alcoholics.     

Alcohol and Expectancy: subjective, psychophysiological and behavioral responses to alcohol stimuli in severely, moderately and non-dependent drinkers

Thirty male subjects, 10 severely and 10 moderately alcohol dependent, along with 10 non-dependent controls, were studied in four experimental drinking conditions. Each subject participated in each condition. All subjects received a priming dose of 2 ml 40% vodka/kg or placebo, and a drinking test of 1 ml 40% vodka/kg 45 minutes later. Subjects were told that the priming dose contained ‘alcohol’ in two conditions and ‘soft drinks’ in the two other conditions of the Balanced placebo design. Self-reported desire for a drink and experienced effects from alcohol were more influenced by instructions than by the actual presence of alcohol, although a peak BAG of 0.11% were reached if all available alcohol were consumed (not all subjects did so). Severely dependent subjects demonstrated more craning than the other groups, this difference was observed in the presence of information about alcohol, regardless of whether alcohol was present or not. No differences in speed of drinking were found. The severely dependent subjects showed a higher general arousal than moderately and non-dependent subjects in this experimental setting, as measured by skin conductance level, and they displayed a higher skin conductance response to the instruction that alcohol was to be given. Severely dependent subjects showed a hypothermic response to alcohol. The results confirm our previous findings that expectations of alcohol exerts greater influence on craving than pharmacological effects of alcohol, but the severely dependent subjects are reacting more strongly to alcohol cues than less dependent alcoholics. In addition, the experiment demonstrates that psychophysiological responses are elicited by alcohol cues, and supports a classical conditioning model of alcohol dependence.     

An Initial Study of the Relationship Between Platelet Adenylyl Cyclase Activity and Alcohol Use Disorder Criteria

Low platelet adenylyl cyclase (AC) activity has been previously proposed to be a trait marker reflecting a genetic predisposition to alcohol dependence. To determine whether low platelet AC activity in alcohol-dependent subjects may be related to specific diagnostic criteria of DSM-IV and ICD-10 alcohol use disorders, we analyzed responses obtained in structured clinical interviews of 36 subjects who were determined to be alcohol-dependent. Platelet AC activity when stimulated by guanylyl-imidodiphosphate [Gpp(NH)p] or fors-kolin was significantly lower in alcohol-dependent subjects as a group, compared with controls. When we analyzed the responses of the alcohol-dependent subjects to questions used to establish the diagnosis of alcohol abuse/dependence and dichotomized the subjects by positive or negative responses, we found that Gpp(NH)p-and forskolin-stimulated platelet AC activities were significantly lower among those alcohol-dependent subjects who had positive responses to questions related to drinking despite negative effects on mood (“Did you ever continue to drink even though you knew it was making you feel depressed, uninterested in things, or suspicious or distrustful of other people?”), drinking despite negative effects on health (“Did you ever continue to drink even though you knew it was causing you a health problem or making a health problem worse?”), or violence when drinking (“Did you get into physical fights while drinking or right after drinking?”). The alcohol-dependent subjects who had negative responses to these questions exhibited Gpp(NH)p-and forskolin-stimulated platelet AC activity that did not differ significantly from values in control subjects. The DSM-IV diagnosis of antisocial personality disorder did not distinguish alcohol-dependent subjects with regard to platelet AC activity. Gpp(NH)p and forskolin-stimulated AC activity may distinguish certain subtypes of alcoholics (i.e., those who develop negative mood in response to drinking, those who continue drinking despite health effects, and those who become violent while drinking).     

Effect of tryptophan depletion on alcohol cue-induced craving in abstinent alcoholic patients

BACKGROUND: The capacity of alcohol cues to precipitate the desire to drink may be an important determinant of relapse to alcohol use in recovering alcohol-dependent patients. This study evaluated whether attenuation of serotonin synthesis via depletion of its precursor tryptophan reduces the magnitude of cue-induced craving for alcohol in recently abstinent alcoholic individuals. METHODS: Alcohol-dependent patients (n = 16), 1 to 3 months after detoxification, who exhibited a 20% or greater increase in reported craving when presented with an alcoholic beverage, completed two additional alcohol cue-exposure test days, 1 week apart. Each cue exposure was preceded by administration of a concentrated amino acid drink that resulted in a rapid and significant decline in plasma free tryptophan (active depletion, no tryptophan supplementation) or a similar drink containing tryptophan (placebo depletion). Tests were conducted in a randomized, double-blind fashion. RESULTS: There were no significant changes in the magnitude of cue-induced craving with active tryptophan depletion compared with placebo. CONCLUSIONS: These data question the dependence of alcohol cue-induced craving in sober alcoholics on the ongoing synthesis of serotonin.     

Evidence for an Interaction Between Age at First Drink and Genetic Influences on DSM-IV Alcohol Dependence Symptoms

Background:  Research suggests that individuals who start drinking at an early age are more likely to subsequently develop alcohol dependence. Twin studies have demonstrated that the liability to age at first drink and to alcohol dependence are influenced by common genetic and environmental factors, however, age at first drink may also environmentally mediate increased risk for alcohol dependence. In this study, we examine whether age at first drink moderates genetic and environmental influences, via gene × environment interactions, on DSM-IV alcohol dependence symptoms.
Methods:  Using data on 6,257 adult monozygotic and dizygotic male and female twins from Australia, we examined the extent to which age at first drink (i) increased mean alcohol dependence symptoms and (ii) whether the magnitude of additive genetic, shared, and nonshared environmental influences on alcohol dependence symptoms varied as a function of decreasing age. Twin models were fitted in Mx.
Results:  Risk for alcohol dependence symptoms increased with decreasing age at first drink. Heritable influences on alcohol dependence symptoms were considerably larger in those who reported an age at first drink prior to 13 years of age. In those with later onset of alcohol use, variance in alcohol dependence was largely attributable to nonshared environmental variance (and measurement error). This evidence for unmeasured gene × measured environment interaction persisted even when controlling for the genetic influences that overlapped between age at first drink and alcohol dependence symptoms.
Conclusions:  Early age at first drink may facilitate the expression of genes associated with vulnerability to alcohol dependence symptoms. This is important to consider, not only from a public health standpoint, but also in future genomic studies of alcohol dependence.     

Human μ-Opioid Receptor Variation and Alcohol Dependence

μ-Opioid receptor-mediated neurotransmission is involved in the reward, tolerance, and withdrawal effects of alcohol. The present association study tested the hypothesis that the common Asn40Asp substitution polymorphism in the N-terminal domain of the human fi-opioid receptor (OPRM) confers vulnerability to subtypes of alcohol dependence. The genotypes of the AsrvWAsp substitution polymorphism were assessed in 327 German alcohol-dependent subjects (according to ICD-10) and in 340 control subjects of German descent, using an assay based on allele-specific polymerase chain reaction. To select alcoholics with a presumed high genetic load, three subgroups were delineated, marked by (1) a family history of parental alcoholism ( n = 114); (2) the inability to abstain from alcohol before the age of 26 years (n = 73); and (3) a history of alcohol withdrawal seizure or delirium (n = 107). The frequency of the Asp40 allele did not differ significantly between the controls [f(Asp40) = 0.078] and either the entire group of alcoholics [f(Asp40) = 0.107; p = 0.066], or the alcoholics with parental alcoholism [f(Asp40) = 0.114; p = 0.094], or the early-onset alcoholics [f (Asp40) = 0.096; p = 0.471] or the alcoholics with severe withdrawal symptoms [f(Asp40) = 0.098; p = 0.350]. Our results do not provide evidence that the common Asn40Asp substitution polymorphism of the OPRM gene contributes a major effect to the pathogenesis of alcohol dependence. Key Words: Alcohol Dependence, OPRM fi-Opioid Receptor, Association, Genetics.     

Alcohol urges in alcohol-dependent drinkers: further validation of the Alcohol Urge Questionnaire in an untreated community clinical population

ABSTRACT Background Alcohol craving is a key element of the alcohol dependence syndrome. However, there is a lack of consensus about the precise nature of craving and the most appropriate method of measurement. Alcohol urges measured by the Alcohol Urge Questionnaire showed a unidimensional structure and evidence of validity and reliability in a US clinical population. The main aim of this study was to establish the validity of the AUQ in an untreated UK clinical population, and its relationships to drinking and personality factors. Subjects All subjects (n = 80) were alcohol‐dependent (DSM‐IV) and presenting for pre‐treatment assessment at a community alcohol team in South‐west ­London. Method All subjects completed the AUQ, Severity of Alcohol Dependence ­Questionnaire (SADQ), Spielberger's State Trait Anxiety Inventory (STAI) and Eysenck Personality Questionnaire (EPQ) and provided a breath specimen for alcohol analysis (BAL). Results Principal components analysis of AUQ revealed one factor which accounted for 69% of variance with high interitem correlations, and an alpha reliability of 0.93. AUQ was significantly correlated with SADQ, BAC, state and trait anxiety and negatively correlated with time since last drink. There were no significant correlations between AUQ and any of the EPQ subscales. SADQ was correlated with neuroticism, but not other EPQ subscales. A regression analysis showed that only SADQ, time since last drink and BAL were significant predictors of alcohol urges. Conclusions This study confirmed the AUQ factor structure and provided further evidence for the validity of AUQ. The relationship between BAL and urges deserves further research. The results did not support the contention that ­anxiety and personality factors predict urges when drinking‐related variables, which also predict urges, are controlled for. The AUQ is a useful measure for clinical and experimental alcohol craving research.     

Multiple Previous Alcohol Detoxifications Are Associated With Decreased Medial Temporal and Paralimbic Function in the Postwithdrawal Period

BACKGROUND: Functional neuroimaging studies after alcohol cessation have demonstrated that chronic alcohol use globally reduces neuronal activity for several weeks. Less is known about the effects of previous alcohol use patterns on regional brain activity. Multiple previous alcohol detoxifications are associated with a worse clinical course and increased risk of seizures, perhaps due to sensitization of key brain structures. We performed the following imaging study in alcoholics in the postwithdrawal period to determine if blood flow in medial temporal structures would differ as a function of previous alcohol use (i.e., whether regions were kindled or sensitized due to multiple detoxifications). METHODS: Fourteen adults meeting DSM-IV criteria for alcohol dependence (mean age 35, 8 SD; 10 men) and participating in a double-blind detoxification medication study underwent a brain perfusion Tc99 m-ECD (Neurolite) single photon emission computed tomography scan on days 7 through 9 (mean 7.6, .5 SD) after their last drink and 2 to 3 days since their last detoxification medication. Seven nonpsychiatrically ill, nonalcohol-dependent healthy adults were scanned as control subjects. RESULTS: Alcoholics compared with controls had widely reduced relative activity in cortical secondary association areas and relatively increased activity in the medial temporal lobes (p < 0.01). Five alcoholic patients with > or = 2 previous detoxifications were compared with five patients in their first detoxification (age and detoxification medication matched). Multiple detoxification patients had significantly lower relative activity in bilateral anterior temporal poles and medial temporal lobes and in visual cortex (p < 0.01) compared with first episode patients. CONCLUSIONS: These studies are consistent with other studies comparing alcoholics and controls. They also suggest that on day 7 of detoxification, alcoholic subjects with multiple previous detoxifications have decreased visual cortex, medial temporal lobes, and anterior paralimbic blood flow, compared with those in their first detoxification. Further studies seem warranted to confirm these initial exploratory results.     

Family history of alcoholism and psychiatric co-morbidity in Brazilian male alcoholics and controls

The present study was aimed at replicating, in a sample of Brazilian subjects, findings generated mostly in developed countries on the relative prevalence of alcohol problems, associated psychiatric disorders, family history of alcoholism and other familial psychiatric disorders in alcoholics and controls. A group of Brazilian male alcoholics (n =103) and controls (n =63) at first admission to ambulatory or inpatient treatment were interviewed individually using sections of the Structured Clinical Interview for DSM-III-R. Information on demographic characteristics, alcohol-related problems, psychiatric problems and family history of alcoholism and depression were collected from all subjects. Alcoholics had a higher prevalence of a family history of alcoholism, a family history of depression and of a personal history of other psychiatric disorders when compared to controls. Comparisons between FHP and FHN alcoholics, although preliminary, showed few significant differences between these subgroups. Comparisons between FHP and FHN controls showed a non-significant trend towards a higher prevalence of psychiatric problems and towards antisocial behaviours among those with a positive family history of alcoholism. The findings point to the importance of cross-cultural studies on genetic and environmental factors related to alcohol dependence.     

Aripiprazole effects on alcohol consumption and subjective reports in a clinical laboratory paradigm--possible influence of self-control

Introduction: There has been increasing interest in the use of medications that affect the dopamine receptor in the treatment of alcoholism. Aripiprazole has the unique pharmacology of being a partial dopamine agonist serving to stabilize brain dopamine systems in both frontal cortical and subcortical areas. As such, it might act to dampen alcohol reinforcement and craving and/or alter control over alcohol use. The current clinical laboratory study was conducted to evaluate the safety and efficacy of aripiprazole as a potential agent to alter drinking and objective effects of alcohol. Methods: Thirty nontreatment seeking alcoholics were enrolled in a subacute human laboratory study and received double‐blind treatment with up to 15 mg of aripiprazole (n = 15) or identical placebo (n = 15) for 8 days. Tolerability and utility of aripiprazole was monitored during natural drinking over the first 6 days of medication treatment and also during a free choice limited access alcohol consumption paradigm following an initial drink of alcohol in a bar‐lab setting on Day 8. Results: Aripiprazole was well tolerated and reduced drinking in nontreatment seeking alcoholics over 6 days of natural drinking—especially in those with lower self control (more impulsive). It also reduced drinks in the bar‐lab after a priming drink and broke the link between priming drink induced stimulation and further drinking. During the bar‐lab drinking session, there were no differences in subjective high, intoxication, or craving between subjects treated with aripiprazole or placebo. Discussion: This study joins several others in demonstrating the utility of subacute dosing laboratory paradigms for evaluating medication effects in alcoholics. Aripiprazole was well tolerated and lowered alcohol use, especially in those with lower impulse control. Further study is needed to determine the safety and utility of aripiprazole in the treatment of alcoholism and if subgroups of alcoholics are more likely to respond.     

The Self-Rating of the Effects of Alcohol (SRE) form as a retrospective measure of the risk for alcoholism

Aims. A low level of response (LR) to alcohol is a characteristic of sons of alcoholics and predicts an elevated future alcoholism risk. A 12-question Self-Rating of the Effects (SRE) of alcohol form has been shown to correlate cross-sectionally with a designation of a low LR determined by alcohol challenges. Design. his study evaluates the potential usefulness of the SRE as a retrospective measure of both the response to alcohol and of subsequent alcoholism in two samples. Setting. All subjects were studied in the United States, most in California. Participants. First, 94 sons of alcoholics and controls completed the SRE 15 years after an alcohol challenge, and SRE values were compared to their prior LR results and their alcoholic outcomes. Secondly, the relationship between SRE results and alcoholic status was determined in 551 men and women alcoholics, their relatives, and controls. Measurements. Subjects were evaluated with face-to-face interviews. Findings. Despite the interval of 15 years, the correlation between the SRE and the subjective high feelings on the alcohol challenge was between -0.3 and -0.4. For those 94 subjects the full SRE correlated with a diagnosis of alcohol dependence at 0.5, a figure that remained at 0.3 even when only the estimates related to the earliest drinking experiences were considered. For the 551 men and women, the correlation between the SRE and alcohol dependence diagnoses was 0.6, including 0.3 for the estimates of the first five times of drinking. All major findings in both samples remained robust when the recent drinking history or the number of items endorsed was considered, or when the most severe alcohol problem, passing out, was deleted from the analysis. Conclusions. When alcohol challenges are not possible, these retrospective reports indicate that the SRE is a potentially useful surrogate for determining a subgroup of people who might carry a low level of response to alcohol and a subsequent elevated risk for alcoholism.     

Regional Brain Metabolic Response to Lorazepam in Alcoholics during Early and Late Alcohol Detoxification

Changes in GABA function have been postulated to be involved in alcohol tolerance, withdrawal and addiction. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission), in alcoholics during early and late withdrawal. Brain metabolism was measured using PET and 2-deoxy-2[¹⁸F]fluoro-D-glucose after placebo (baseline) and after lorazepam (30 μg/kg intravenously) in 10 alcoholics and 16 controls. In the alcoholics evaluations were performed 2 to 3 weeks after detoxification and were repeated 6 to 8 weeks later. Controls were also evaluated twice at a 6 to 8 weeks interval. While during the initial evaluation metabolism was significantly lower for most brain regions in the alcoholics than in controls in the repeated evaluation the only significant differences were in cingulate and orbitofrontal cortex. Lorazepam-induced decrements in metabolism did not change with protracted alcohol withdrawal and the magnitude of these changes were similar in controls and alcoholics except for a trend towards a blunted response to lorazepam in orbitofrontal cortex in alcoholics during the second evaluation. Abnormalities in orbitofrontal cortex and cingulate gyms in alcoholics are unlikely to be due to withdrawal since they persist 8 to 11 weeks after detoxification. The fact that there was only a trend of significance for an abnormal response to lorazepam in orbitofrontal cortex indicates that mechanisms other than GABA are involved in the brain metabolic abnormalities observed in alcoholic subjects.     

Alcohol Expectancies in a Native American Population

Native Americans, as a group, have a high prevalence of alcohol abuse and alcohol dependence, although specific risk factors for alcoholism among this population have yet to be clearly identified. One set of factors that may contribute to the development of alcoholism are expectations of alcohol's effects. Previous research has shown that heavy drinkers and alcoholics have higher alcohol-related expectancies. Some studies have also shown an association between alcohol expectancies and a positive familial history of alcoholism. To examine factors that are related to expectations of alcohol's effects in a Native American population, this study evaluated healthy, nonalcoholic Mission Indian men between the ages of 18 and 25 years using the short form of the Alcohol Expectancy Questionnaire (AEQ). The influence of recent drinking history, family history of alcoholism, and degree of Native American heritage on alcohol-related expectancies was determined using regression analyses for the total AEQ score and for each of the six AEQ subscales. Recent drinking history accounted for a significant proportion of the variance in the total score, as well as scale I (global positive changes) and scale VI (arousal and power) of the AEQ. Degree of Native American heritage and family history of alcoholism did not account for a significant amount of variability in alcohol expectancies. These results suggest that, consistent with findings in other populations, alcohol expectancies are related to drinking patterns in Mission Indians. However, no association with two other potential risk factors were found in this sample of Native Americans.     

Alcohol Dependence Among General Medical Inpatients

Alcoholics identified on medical wards were found to be less severely dependent overall than comparative samples admitted to a psychiatric hospital for treatment. This was the case although typical alcohol consumption levels were reported to be the same. Few ‘medical’alcoholics conformed to Jellinek's beta subtype and few were severely dependent. There was, however, on the scale of severity of dependence a similar distribution of cases of ‘absent to minimal’—‘mild to moderate’dependence between ‘medical’ alcoholics and approximately half of ‘psychiatric’ alcoholics. The remaining ‘psychiatric’ alcoholics were more severely dependent. The development of dependence as judged by the temporal ordering of symptoms occurred according to a sequence which was similar to that identified in psychiatric treatment settings.     

Hormonal, Psychological, and Alcohol Craving Changes after m-Chlorophenylpiperazine Administration in Alcoholics

To assess the serotonergic function of alcoholics, their neuroendocrine and psychological responsivities to the serotonergic partial agonist meta-chlorophenylpiperazine (m-CPP) was compared with the responsitivity of healthy subjects. The effect of m-CPP on craving for alcohol was also assessed in the alcoholics. Sixteen patients and 14 controls were tested under double-blind, placebo-controlled conditions. m-CPP (0.5 mg/kg of body weight) was given orally. Alcoholics were tested after a period of abstinence of 15 to 39 days. The two groups of subjects did not differ in their cortisol response to m-CPP, but the prolactin response of alcoholics was significantly blunted. Alcoholics reported a significantly more intense "high" feeling after m-CPP than the healthy subjects. m-CPP induced also a decreased craving for alcohol. Our data thus provide further evidence for the existence of a serotonergic dysfunction in alcoholics and a modulation of craving for alcohol by serotonergic systems.     

Psychophysiological Indicators of Craving in Alcoholics: Effects of cue exposure

Autonomic arousal, as indicated by Skin Conductance, and heart rate parameters, was evaluated in 16 detoxified male alcoholics before and after intake of a standard priming dose of alcohol/soft drink. After priming, patients were given cue exposure, i.e. presentations of preferred beverage bottles containing original content or non-alcohol fluid of identical visual appearance. This was followed by response prevention training. All patients participated during six identical sessions. Patients given alcohol before cue exposure showed higher levels of arousal, throughout all sessions. Immediately after alcohol intake, increases in skin conductance level and number of spontaneous skin conductance responses were observed for all sessions. This pattern was most pronounced in the first session. Skin conductance parameters showed a decrease towards baseline levels over repeated cue exposure sessions. A similar pattern was also evident for the subjective indicators of arousal.