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Abstract Background Aldehyde dehydrogenase 2 (ALDH2) is critical for alcohol metabolism by converting acetaldehyde to acetic acid. In East Asian descendants, an inactive genetic variant in ALDH2, rs671, triggers an alcohol flushing response due to acetaldehyde accumulation. As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays. Methods After IRB approval, human subjects were given an alcohol challenge (0.25 g/kg) while quantifying acetaldehyde levels and the physiological response (heart rate and skin temperature) to alcohol. Further, by employing biochemical techniques including human purified ALDH2 proteins and transiently transfected NIH 3T3 cells, we characterized two newly identified ALDH2 variants for ALDH2 enzymatic activity, ALDH2 dimer/tetramer formation, and reactive oxygen species production after alcohol treatment. Results Humans heterozygous for rs747096195 (R101G) or rs190764869 (R114W) had facial flushing and a 2-fold increase in acetaldehyde levels, while rs671 (E504K) had facial flushing and a 6-fold increase in acetaldehyde levels relative to wild type ALDH2 carriers. In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased Vmax for both R101G and R114W. Transiently transfected NIH-3T3 cells with R101G and R114W also had a reduced enzymatic activity by ~ 50% relative to transfected wild-type ALDH2 and when subjected to alcohol, the R101G and R114W variants had a 2-3-fold increase in reactive oxygen species formation with respect to wild type ALDH2. Conclusions We identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. As alcohol use is associated with a several-fold higher risk for esophageal cancer for the E504K variant, the methodology developed here to characterize ALDH2 genetic variant response to alcohol can lead the way precision medicine strategies to further understand the interplay of alcohol consumption, ALDH2 genetics, and cancer.

Background: Aldehyde dehydrogenase 2 (ALDH2) is critical for alcohol metabolism by converting acetaldehyde to acetic acid. In East Asian descendants, an inactive genetic variant in ALDH2, rs671, triggers an alcohol flushing response due to acetaldehyde accumulation. As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays. Methods: After IRB approval, human subjects were given an alcohol challenge (0.25 g/kg) while quantifying acetaldehyde levels and the physiological response (heart rate and skin temperature) to alcohol. Further, by employing biochemical techniques including human purified ALDH2 proteins and transiently transfected NIH 3T3 cells, we characterized two newly identified ALDH2 variants for ALDH2 enzymatic activity, ALDH2 dimer/tetramer formation, and reactive oxygen species production after alcohol treatment. Results: Humans heterozygous for rs747096195 (R101G) or rs190764869 (R114W) had facial flushing and a 2-fold increase in acetaldehyde levels, while rs671 (E504K) had facial flushing and a 6-fold increase in acetaldehyde levels relative to wild type ALDH2 carriers. In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased Vmax for both R101G and R114W. Transiently transfected NIH-3T3 cells with R101G and R114W also had a reduced enzymatic activity by ~ 50% relative to transfected wild-type ALDH2 and when subjected to alcohol, the R101G and R114W variants had a 2-3-fold increase in reactive oxygen species formation with respect to wild type ALDH2. Conclusions: We identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. As alcohol use is associated with a several-fold higher risk for esophageal cancer for the E504K variant, the methodology developed here to characterize ALDH2 genetic variant response to alcohol can lead the way precision medicine strategies to further understand the interplay of alcohol consumption, ALDH2 genetics, and cancer. [ABSTRACT FROM AUTHOR]

HIV/AIDS remains a significant health threat and alcohol is a robust contributing factor. After 25 years of alcohol challenge studies investigating alcohol-related behavioral risk (ARBR), much has been learned delineating how drinking influences sexual transmission. We examine this research and consider its relevance for interventions in the era of antiretrovirals. We consider prototypic alcohol challenge methods, illustrative findings, and prevention/intervention implications, noting three perspectives: (a) scale up/extend existing interventions, including identifying under-targeted risk groups and intersecting with PrEP/PEP interventions; (b) modify existing interventions by cultivating psychoeducational content related to alcohol expectancies, alcohol myopia, sexual arousal, risk perception, sexual abdication, and condom use resistance; and (c) innovate new interventions through Science of Behavior Change approaches and repurposing ARBR paradigms. Finally, we suggest research directions concluding that until HIV incidence diminishes significantly, psychosocial interventions addressing the nexus of alcohol use, sexual transmission, and adherence to biomedical protocols will be an important priority. [ABSTRACT FROM AUTHOR]

BackgroundKoob's allostatic model of addiction emphasizes the transition from positive reinforcement to negative reinforcement as dependence develops. This study seeks to extend this well-established neurobiological model to humans by examining subjective response to alcohol (SR) as a biobehavioral marker of alcohol reinforcement. Specifically, this study examines (a) differential SR in heavy drinkers (HDs) vs. alcohol dependent individuals (ADs) and (b) whether HDs and ADs differ in terms of the association between SR and craving.MethodsData was culled from two alcohol challenge studies, totalling 91 participants (oversampled on OPRM1 Asp40 carriers). Alcohol was administered intravenously and participants completed standard measures of SR and craving at BrAC's of 0.02, 0.04, and 0.06 g/dl. SR was modeled as a multi-dimensional construct consisting of stimulation, sedation, and tension relief.ResultsADs reported significantly higher sedation and craving initially and exhibited a blunted response to alcohol along escalating BrACs. ADs exhibited greater initial tension but did not differ from HDs in tension reduction across rising BrACs. Further, alcohol-induced stimulation was associated with alcohol craving to a significantly greater degree in HDs, as compared to ADs.ConclusionsThis study provides initial evidence that HDs and ADs differ in their subjective experience of alcohol and in the association between dimensions of SR and craving for alcohol. Hypotheses derived from the allostatic model were partially supported, such that, while ADs and HDs did not differ on stimulation response, there was a relative dissociation between positive reinforcement and craving in ADs as compared to HDs.

Background: Koob's allostatic model of addiction emphasizes the transition from positive reinforcement to negative reinforcement as dependence develops. This study seeks to extend this well-established neurobiological model to humans by examining subjective response to alcohol (SR) as a biobehavioral marker of alcohol reinforcement. Specifically, this study examines (a) differential SR in heavy drinkers (HDs) vs. alcohol dependent individuals (ADs) and (b) whether HDs and ADs differ in terms of the association between SR and craving. Methods: Data was culled from two alcohol challenge studies, totalling 91 participants (oversampled on OPRM1 Asp40 carriers). Alcohol was administered intravenously and participants completed standard measures of SR and craving at BrAC's of 0.02, 0.04, and 0.06. g/dl. SR was modeled as a multi-dimensional construct consisting of stimulation, sedation, and tension relief. Results: ADs reported significantly higher sedation and craving initially and exhibited a blunted response to alcohol along escalating BrACs. ADs exhibited greater initial tension but did not differ from HDs in tension reduction across rising BrACs. Further, alcohol-induced stimulation was associated with alcohol craving to a significantly greater degree in HDs, as compared to ADs. Conclusions: This study provides initial evidence that HDs and ADs differ in their subjective experience of alcohol and in the association between dimensions of SR and craving for alcohol. Hypotheses derived from the allostatic model were partially supported, such that, while ADs and HDs did not differ on stimulation response, there was a relative dissociation between positive reinforcement and craving in ADs as compared to HDs.

Alcohol use disorder (AUD) is a genetically influenced disease with peak onset in young adulthood. Identification of factors that predict whether AUD symptoms will diminish or persist after young adulthood is a critical public health need. King and colleagues previously reported that acute response to alcohol predicted future AUD symptom trajectory. Genes associated with brain dopamine signaling, which underlies alcohol's rewarding effects, might influence this finding. This study analyzed whether variation at a variable number tandem repeat polymorphism in DAT1/SLC6A3, the gene encoding the dopamine transporter, moderated the predictive relationships between acute response to alcohol and future AUD symptoms among participants enrolled in the Chicago Social Drinking Project (first two cohorts). Heavy-drinking young adults (N = 197) completed an alcohol challenge, in which acute response (liking, wanting, stimulation, and sedation) was measured. Alcohol use disorder symptoms were assessed over the following 6 years. DAT1 genotype significantly moderated the interactions between follow-up time and alcohol liking (P = 0.006) and wanting (P = 0.006) in predicting future AUD symptoms. These predictive effects were strongest among participants who carried the DAT1 9-repeat allele, previously associated with enhanced striatal dopamine tone relative to the 10-repeat allele. Exploratory analyses indicated that DAT1 effects on the relationship between alcohol liking and AUD symptoms appeared stronger for females (n = 79) than males (n = 118) (P = 0.0496). These data suggest that heavy-drinking DAT1 9-repeat allele carriers who display high alcohol-induced reward in young adulthood may be predisposed to persistent AUD symptoms and support combining genotypic and phenotypic information to predict future AUD risk. [ABSTRACT FROM AUTHOR]

Impaired control over alcohol is central to alcohol use disorder, but most research on impaired control is limited to self-report methods. This study applied intravenous alcohol self-administration to conduct a preliminary investigation of a novel human laboratory model of impaired control. Heavy episodic drinkers (ages 19-22 years) completed a two-hour intravenous alcohol self-administration session that involved an incentive to maintain breath alcohol concentration below 80 mg%. Impaired control was operationalized based on whether participants exceeded (impaired control positive; IC+) or adhered to (impaired control negative; IC-) the breath alcohol concentration limit, as well as the discrepancy between intended and actual peak breath alcohol concentration. Analyses of subjective processes revealed that IC+ participants tended to underestimate their peak breath alcohol concentration relative to IC- participants. Further, IC+ reported greater craving after an initial priming phase, and craving mediated the relationship between self-report impaired control and discrepancies between intended and actual breath alcohol concentration. IC+ participants also showed stronger within-person associations between state changes in stimulation and momentary alcohol self-administration throughout the session. Laboratory impaired control indices demonstrated convergent validity with an established self-report measure of impaired control. These findings provide preliminary validation of a novel human laboratory model of impaired control in a sample of young heavy episodic drinkers, and offer insight into the role of subjective responses (craving, stimulation) in impaired control. [ABSTRACT FROM AUTHOR]

Background A functional polymorphism within the μ-opioid receptor ( OPRM1) gene, rs1799971 (A118G), previously has been associated with measures of alcohol use and sensitivity to its effects, but findings have been inconclusive. A recent study suggested that a second nearby variant within OPRM1, rs3778150, is robustly associated with heroin dependence and fully explained a smaller observed association with rs1799971. Given evidence that the rs3778150-C allele is associated with decreased OPRM1 expression levels in the human brain, the current study sought to test the hypothesis that rs3778150 represents a causal variant within OPRM1 that increases risk for a variety of alcohol use phenotypes. Methods Participants with genotype and phenotype data from a larger experimental study ( N = 152) were assessed on measures of subjective response to alcohol and alcohol use. Measures included (i) the Self-Rating of the Effects of Alcohol and the Alcohol Sensitivity Questionnaire, (ii) the Biphasic Alcohol Effects Scale ( BAES) and ratings of subjective intoxication, and (iii) average number of drinks per week in the past month. Results Compared to rs3778150-T homozygous individuals, carriers of the rs3778150-C allele exhibited significantly lower retrospective self-report levels of alcohol sensitivity. Carriers of the rs3778150-C allele also exhibited lower levels of BAES alcohol-related stimulation during an alcohol challenge and reported higher levels of drinking in the last 30 days. With the exception of lower levels of BAES alcohol-related sedation, the rs1799971 variant did not show consistent significant association with any of the alcohol phenotypes in the presence of rs3778150. Conclusions Results suggest that rs3778150 may be causally related to alcohol use phenotypes, and could potentially account for previously observed associations of rs1799971 with substance use phenotypes. Future studies may investigate potential causal relations among genetic variants in OPRM1, subjective response to alcohol, and drinking phenotypes to further delineate the effects of rs3778150. [ABSTRACT FROM AUTHOR]

Pre-clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol-dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non-treatment-seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light-to-moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post-alcohol administration. However, stimulation was dose-dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose-dependently associated with and preceded craving among non-dependent HD. [ABSTRACT FROM AUTHOR]

Background Motivational models of alcohol use suggest that individual differences in sensitivity to the acute subjective effects of alcohol play an important role in motivational pathways to alcohol use. However, few studies have examined the link between drinking motives and subjective responses to alcohol. This study investigated the associations of coping and enhancement drinking motives with subjective stimulant and sedative effects during a laboratory alcohol administration session. We also examined whether stimulation and sedation following alcohol administration mediated the relationships between drinking motives and postalcohol ratings of alcohol wanting and liking. Methods Heavy episodic drinkers ( n = 147, ages 19 to 25) at 2 sites participated in an intravenous alcohol administration session in which blood alcohol concentration was raised to a target of 80 mg% over 20 minutes. Participants completed measures of stimulation and sedation at baseline and 20 minutes and also rated alcohol liking and wanting at 20 minutes. Drinking motives and alcohol use were assessed during a previous laboratory visit. Results A path analysis controlling for baseline stimulation and sedation showed that enhancement motives were positively associated with postalcohol stimulation and negatively associated with postalcohol sedation. In contrast, coping motives were positively associated with postalcohol sedation. In turn, postalcohol stimulation, but not sedation, was associated with alcohol wanting and liking. Further, indirect pathways from enhancement motives to postalcohol wanting and liking mediated through postalcohol stimulation were statistically significant. Coping motives, on the other hand, were directly associated with increased postalcohol wanting and liking. Conclusions The results demonstrate that drinking motives are linked with individual differences in sensitivity to the effects of alcohol, which may serve as a mechanism underlying alcohol reinforcement and the motivation to consume more alcohol during a drinking episode. [ABSTRACT FROM AUTHOR]

Background Variability in sensitivity to the acute effects of alcohol is an important risk factor for the development of alcohol use disorder ( AUD). The most commonly used retrospective self-report measure of sensitivity, the Self-Rating of the Effects of Alcohol (SRE) form, queries a limited number of alcohol effects and relies on respondents' ability to recall experiences that might have occurred in the distant past. Here, we investigated the construct validity of an alternative measure that queries a larger number of alcohol effects, the Alcohol Sensitivity Questionnaire ( ASQ), and compared it to the SRE in predicting momentary subjective responses to an acute dose of alcohol. Methods Healthy young adults ( N = 423) completed the SRE and the ASQ and then were randomly assigned to consume either alcohol or a placebo beverage (between-subjects manipulation). Stimulation and sedation (Biphasic Alcohol Effects Scale) and subjective intoxication were measured multiple times after drinking. Results Hierarchical linear models showed that the ASQ reliably predicted each of these outcomes following alcohol but not placebo consumption, provided unique prediction beyond that associated with differences in recent alcohol involvement, and was preferred over the SRE (in terms of model fit) in direct model comparisons of stimulation and sedation. Conclusions The ASQ compared favorably with the better-known SRE in predicting increased stimulation and reduced sedation following an acute alcohol challenge. The ASQ appears to be a valid self-report measure of alcohol sensitivity and therefore holds promise for identifying individuals at-risk for AUD and related problems. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The ability of the Essential Tremor (ET) Rating Assessment Scale (TETRAS) to detect changes in tremor severity is unknown. Methods Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content (brAC). Effects were investigated independently with accelerometry and TETRAS. Results Accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant. TETRAS and accelerometry showed a significant effect of time point using repeated-measures analysis of variance. The difference between baseline and each of the following six time points as well as the correlation of TETRAS with brAC were significant. The calculated minimum detectable change of TETRAS was 8.9% and the effect size was d = 4.75 (95% confidence interval: 3.60-5.90). Conclusion We demonstrated sensitivity to change of the TETRAS performance scale after a therapeutic intervention, which further establishes its potential for use in both clinical and research settings. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

This review provides a qualitative assessment of all known scientific studies on the impact of alcohol ingestion on nocturnal sleep in healthy volunteer's. At all dosages, alcohol causes a reduction in sleep onset latency, a more consolidated first half sleep and an increase in sleep disruption in the second half of sleep. The effects on rapid eye movement (REM) sleep in the first half of sleep appear to be dose related with low and moderate doses showing no clear trend on REM sleep in the first half of the night whereas at high doses, REM sleep reduction in the first part of sleep is significant. Total night REM sleep percentage is decreased in the majority of studies at moderate and high doses with no clear trend apparent at low doses. The onset of the first REM sleep period is significantly delayed at all doses and appears to be the most recognizable effect of alcohol on REM sleep followed by the reduction in total night REM sleep. The majority of studies, across dose, age and gender, confirm an increase in slow wave sleep (SWS) in the first half of the night relative to baseline values. The impact of alcohol on SWS in the first half of night appears to be more robust than the effect on REM sleep and does not appear to be an epiphenomenon REM sleep reduction. Total night SWS is increased at high alcohol doses across gender and age groups. [ABSTRACT FROM AUTHOR]

Background Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism have focused on polymorphisms in alcohol or aldehyde dehydrogenases, we have now tested for association with genes in alternative metabolic pathways that catalyze the carbon skeleton of ethanol ( EtO H) and NADH reoxidation. Methods Nine hundred fifty single nucleotide polymorphisms ( SNPs) spanning 14 genes ( ACN9, ACSS1, ACSS2, ALDH1A1, CAT, CYP2E1, GOT1, GOT2, MDH1, MDH2, SLC25A10, SLC25A11, SLC25A12, SLC25A13) were genotyped in 352 young adults who participated in an alcohol challenge study. Traits tested were blood alcohol concentration (BAC), breath alcohol concentration (BrAC), peak alcohol concentration, and rates of alcohol absorption and elimination. Allelic association was tested using quantitative univariate and multivariate methods. Results A CYP 2 E 1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study-wide significance (4.01 × 10−5) for 2 early BAC, 8 Br AC measures, and the peak Br AC. For each phenotype, the minor C allele was related to a lower alcohol concentration, most strongly for the fourth Br AC ( p = 2.07 × 10−7) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH1 A 1 and on chromosome 17 near SLC25 A 11 for aspects of blood and breath alcohol metabolism. An SNP upstream of GOT1 (rs2490286) reached study-wide significance for multivariate BAC metabolism ( p = 0.000040). Conclusions Overall, we did not find strong evidence that variation in genes coding for proteins that further metabolize the carbon backbone of acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH, affects alcohol metabolism in our European-descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP2 E 1 may play a role in preabsorptive or early hepatic alcohol metabolism, but more samples are required to validate this finding. [ABSTRACT FROM AUTHOR]

Abstract: Objective: In the following study we tested the stress response dampening (SRD) model which postulates that stress responses are more likely to be attenuated by alcohol in individuals at risk for alcohol dependence than in persons without that risk. In a laboratory experiment we examined a) if SRD effects exist for both sons and healthy daughters of alcohol dependent fathers, and b) if SRD effects exist for siblings of alcohol dependent males. Methods: We recruited 104 subjects at risk and 51 matched control subjects. In a laboratory experiment, study subjects received alcohol in one of two laboratory sessions and a stress paradigm served to elicit heart rate stress responses. Results: Heart rate stress responses were attenuated by alcohol in female family history positive (FHP) and female family history negative (FHN) subjects, however not in males. A multiple regression analysis revealed “Heart Rate Stress Response in the Non-Alcohol Condition” and “Blood Alcohol Level” as significant predictors of SRD. Conclusions: According to our findings, females carry a distinct risk for developing alcohol dependence, regardless of their family history and regardless of their degree of familial relationship. This is an important issue for devising models concerning the development and maintenance of alcohol dependence in females. The study extends the current research literature, which mainly focuses on male subjects at risk, by including female subjects at risk, as well as siblings at risk of both genders. [Copyright &y& Elsevier]

Abstract: cognitive processing model postulates that craving will only occur when access to alcohol is blocked. To test a hypothesis based on this model, we analyzed data from a naturalistic laboratory alcohol challenge study involving moderate-to-heavy drinking young adults (N =174) with a focus on the placebo beverage condition of this study. Our hypothesis was that self-reports of “wanting more alcohol” (i.e., craving) in the lab, following placebo, would predict subsequent ad libitum consumption because placebo administration would constitute partial blocking of access to alcohol. We also tested the possibility that craving might mediate associations between personality traits and ad libitum consumption. Both trait disinhibition and reports of craving following the placebo beverage significantly predicted ad libitum consumption. Further, craving partially mediated the association between trait disinhibition and ad libitum consumption. Potential implications of these findings are discussed. [Copyright &y& Elsevier]

Individual differences in subjective alcohol effects have been shown to differ by risk status (e.g., family history of alcoholism) and to predict future risk for alcohol-related problems. Presumably, individual differences in both stimulant and sedative responses affect the rewarding value of drinking which, in turn, impacts future drinking behavior. Although plausible, this theoretical model is largely untested. The current study attempted to provide experimental evidence for the impact of subjective alcohol responses on within session drinking behavior. Using a placebo-controlled between-subjects alcohol administration paradigm, experiences and evaluations of stimulant and sedative alcohol effects (after a target dose of 0.06 g%) were assessed as predictors of ad-libitum consumption in the context of anticipatory stress. Analyses indicated that an initial dose of alcohol increased experiences of both stimulation and sedation although stimulant effects were evaluated much more positively. In addition, stimulant effects after a priming dose predicted further consumption, whereas sedative effects did not. At least among moderate to heavy drinking college students, stimulant alcohol effects are more reinforcing and predict within session drinking behavior under social stress. Increased attention should be given to stimulant alcohol effects as a risk factor for excessive consumption in this population. Incorporating information about stimulant alcohol effects in prevention and intervention programs may also be important if additional research supports the current results. [ABSTRACT FROM AUTHOR]

Background: Topiramate was recently reported to be efficacious in reducing drinking rates and craving among individuals with alcohol dependence in a randomized controlled trial, but dose effects could not be determined. This laboratory study systematically examined the dose-dependent effects of topiramate on cue-elicited craving and other putative mechanisms of its pharmacotherapeutic effects on drinking. Methods: Male and female heavy drinkers ( n = 61) were randomized to 1 of 3 medication conditions (200 mg/d; 300 mg/d; placebo) in a double-blind study. Participants reached the target dose after a 32-day titration period, then were stabilized for approximately 1 week. All then participated in a laboratory assessment of alcohol cue reactivity and of the subjective effects of a moderate dose of alcohol. Results: Both doses of topiramate reduced the frequency of heavy drinking during the titration period as compared to placebo. However, topiramate did not affect self-reported craving for alcohol during the titration period, during the cue reactivity protocol, or in response to the alcohol challenge procedure. Topiramate reduced the stimulating effects of alcohol ingestion compared to placebo, but only in the 200 mg group. Conclusions: The results of this study support previous findings that topiramate reduces drinking, but the behavioral mechanism underlying this effect does not appear to be attenuation of craving for alcohol as measured using the approaches employed in this study. Rather, the results tentatively suggest that topiramate may exert its beneficial effects by altering the subjective experiences of alcohol consumption. Limitations of the current study are discussed and complementary methods are recommended for future studies, such as the use of behavioral economic paradigms and ecological momentary assessment. [ABSTRACT FROM AUTHOR]

Background: Previous research suggests that high levels of anxiety sensitivity (AS; fear of anxiety symptoms) may constitute a risk factor for alcohol abuse. The present study evaluated the hypothesis that high AS levels may increase risk for alcohol abuse by promoting a heightened sober reactivity to theoretically relevant stressors and heightened sensitivity to alcohol's emotional reactivity dampening effects, which would negatively reinforce drinking in this population. Methods: One hundred and two undergraduate participants (51 high AS, 51 low AS) with no history of panic disorder were assigned to either a placebo, low-dose alcohol, or high-dose alcohol beverage condition (17 high AS, 17 low AS per beverage condition). After beverage consumption and absorption, participants underwent a 3 min voluntary hyperventilation challenge. Results and Conclusions: High-AS/placebo participants displayed greater affective and cognitive reactivity to the challenge than low-AS/placebo participants, which indicated increased fear and negative thoughts (e.g., 'losing control') during hyperventilation among sober high AS individuals. Dose-dependent alcohol dampening of affective and cognitive reactivity to hyperventilation was observed only among high-AS participants, which suggested that high-AS individuals may be particularly sensitive to alcohol-induced reductions in their degree of fear and negative thinking in response to the experience of physical arousal sensations. In contrast, dose-dependent alcohol dampening of self-reported somatic reactivity was observed among both high- and low-AS participants. We discuss implications of these results for understanding risk for alcohol abuse in high-AS individuals, as well as directions for future research. [ABSTRACT FROM AUTHOR]

In an earlier analysis, men and women who were current or former smokers were found to report feeling less intoxicated on average than nonsmokers after ingestion of a challenge dose of alcohol. Here, we examine whether differences in subjective response to alcohol and a tendency to smoke cigarettes are transmitted together in families; and, if so, whether this association might be entirely explained by the same heritable factors that influence alcohol intake (as we might expect if both smoking and subjective intoxication are influenced by some general susceptibility for substance use). Alcohol challenge data on 388 Australian male and female twins (194 complete pairs) were reanalyzed using multivariate genetic analysis to evaluate the association between cigarette smoking and self-report intoxication after a standard dose of alcohol. In women, we could not reject the hypothesis of complete genetic overlap between effects on intoxication rating and history of smoking, and a significant residual genetic correlation between smoking and postalcohol intoxication persisted even when genetic influences on alcohol consumption were controlled for. In men, the familial association seemed to be largely environmentally mediated and associated with differences in drinking history. These findings prompt the question of whether, in some individuals, cigarette smoking may contribute to the development of tolerance to the effects of alcohol. [ABSTRACT FROM AUTHOR]

Many studies have found genetic effects to contribute to alcoholism risk in both men and women. Based on preliminary evidence for shared genetic risk between smoking and drinking problems, a re-analysis of alcohol challenge data on 412 Australian twins was performed to explore the possibility that smoking may diminish or moderate the intoxicating effects of alcohol. We found history of smoking to be strongly associated with self-reported intoxication after alcohol challenge in women (women: r = -0.44 ± 0.08; men: r = -0.21 ±0.08), comparable with self-reported average weekly consumption of alcohol, which was more strongly associated in men (women: r = -0.37 ±0.07; men: r = -0.54 ±0.06). Structural equation model-fitting indicated a strong association between heavy drinking and smoking, but the association between smoking and postalcohol intoxication remained even when the effects of heavy drinking were controlled for. These results prompt the question of whether smoking cigarettes directly influences the transition from moderate to excessive use of alcohol by diminishing feelings of alcohol intoxication. [ABSTRACT FROM AUTHOR]

We examined the hypothesis that genetically determined differences in sensitivity to alcohol explain some of the genetic variation in alcohol consumption pattern. Self-report data on average weekly alcohol consumption and self-ratings of intoxication after a standard dose of ethanol (0.75 g/kg body weight), used as an index of sensitivity, were obtained on 206 Australian twin pairs. Significant genetic covariance between weekly consumption and level of intoxication after alcohol intake was found in males, lower ratings of intoxication being associated with increased consumption. However, when direction of causation models were fitted to the male twin data, the hypothesis that decreased sensitivity was a cause of increased consumption was rejected. The major causal effect was that of weekly consumption on level of sensitivity. A similar, although nonsignificant, trend was observed in females. The strength of the association between self-report of average weekly consumption and level of intoxication after a standard dose of alcohol supports the validity of the former measure. [ABSTRACT FROM AUTHOR]

Despite a number of approved medications for alcohol use disorder (AUD), this chronic relapsing disease still produces a considerable global burden, with both health-related and financial consequences. While clinical trials are a critical step in drug development, human laboratory studies provide the field with means of screening pharmacotherapy for more nuanced aspects of AUD. Specifically, studies employing alcohol administration techniques (e.g., alcohol challenge and self-administration) are able to investigate potential drugs with respect to their ability to alter various responses to alcohol administration or alter alcohol consumption in laboratory settings. This chapter reviews methodological designs and provides updates from alcohol administration studies used to screen for potential AUD pharmacotherapy over the past decade. These recent studies have supported the efficacy of approved drugs, identified some promising novel drugs, and investigated other drugs that appear ineffective in AUD treatment. Yet, few drugs are explored using the different variants of alcohol administration methods, and using the different methods has provided inconsistent results for the same drug. Future research would aid advancement in the field by testing medication with various methodologies and refining recently developed techniques.

Background: Koob's allostatic model of addiction emphasizes the transition from positive reinforcement to negative reinforcement as dependence develops. This study seeks to extend this well-established neurobiological model to humans by examining subjective response to alcohol (SR) as a biobehavioral marker of alcohol reinforcement. Specifically, this study examines (a) differential SR in heavy drinkers (HDs) vs. alcohol dependent individuals (ADs) and (b) whether HDs and ADs differ in terms of the association between SR and craving., Methods: Data was culled from two alcohol challenge studies, totalling 91 participants (oversampled on OPRM1 Asp40 carriers). Alcohol was administered intravenously and participants completed standard measures of SR and craving at BrAC's of 0.02, 0.04, and 0.06 g/dl. SR was modeled as a multi-dimensional construct consisting of stimulation, sedation, and tension relief., Results: ADs reported significantly higher sedation and craving initially and exhibited a blunted response to alcohol along escalating BrACs. ADs exhibited greater initial tension but did not differ from HDs in tension reduction across rising BrACs. Further, alcohol-induced stimulation was associated with alcohol craving to a significantly greater degree in HDs, as compared to ADs., Conclusions: This study provides initial evidence that HDs and ADs differ in their subjective experience of alcohol and in the association between dimensions of SR and craving for alcohol. Hypotheses derived from the allostatic model were partially supported, such that, while ADs and HDs did not differ on stimulation response, there was a relative dissociation between positive reinforcement and craving in ADs as compared to HDs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)