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Background: The COVID‐19 pandemic, caused by the SARS‐CoV‐2 virus, has resulted in illness, deaths and societal disruption on a global scale. Societies have implemented various control measures to reduce transmission of the virus and mitigate its impact. Individual behavioural changes are crucial to the successful implementation of these measures. One commonly recommended measure to limit risk of infection is distancing. It is important to identify those factors that can predict the uptake and maintenance of distancing. Objectives: We aimed to identify and synthesise the evidence on malleable psychological and psychosocial factors that determine uptake and adherence to distancing aimed at reducing the risk of infection or transmission of COVID‐19. Search Methods: We searched various literature sources including electronic databases (Medline ALL, Child Development & Adolescent Studies, ERIC, PsycInfo, CINAHL & Web of Science), web searches, conference proceedings, government reports, other repositories of literature and grey literature. The search strategy was built around three concepts of interest including (1) context (terms relating to COVID‐19), (2) behaviour of interest and (3) terms related to psychological and psychosocial determinants of COVID‐19 Health‐Related Behaviours and adherence or compliance with distancing, to capture malleable determines. Searches capture studies up until October 2021. Selection Criteria: Eligibility criteria included observational studies (both retrospective and prospective) and experimental studies that measure and report malleable psychological and psychosocial determinants and distancing (social and/or physical) at an individual level, amongst the general public. We defined physical distancing as, maintaining the recommended distance from others when physically present. And social distancing being defined as, minimising social contact with those outside of your own household. Screening was supported by the Cochrane Crowd. Studies' titles and abstracts were screened against the eligibility criteria by three independent screeners. Following this, all potentially relevant studies were screened at full‐text level by the research team. All conflicts between screeners were resolved by discussion between the core research team. Data Collection and Analysis: All data extraction was managed in EPPI‐Reviewer software. All eligible studies, identified through full‐text screening were extracted by one author. We extracted data on study information, population, determinant, behaviour and effects. A second author checked data extraction on 20% of all included papers. All conflicts were discussed by the two authors until consensus was reached. We assessed methodological quality of all included studies using an adapted version of the Joanna Briggs Institute Quality appraisal tool. Main Results: A total of 91 studies were suitable for inclusion in the review, representing 199,604 participants. The vast majority of studies had samples from the general public, with 15 of the studies focusing on specific samples. The majority of studies included participants over 18 years old, with 5 reporting on specific ages (adolescents and adults over 65). The quality of 29 of the studies was rated as unclear, 48 were rated as low, and 14 rated high risk of bias, predominately due to lack of reporting of recruitment, sample characteristics and methodology. Overall the majority of these relationships were weak. Stronger relationships were observed between attitudes, social norms, perceived behavioural control and both social and physical distancing. And between worry, response effectiveness, self‐efficacy and social distancing. However, there is a high level of heterogeneity in the findings. This heterogeneity might be, partly, due to the differences in measurement of the determinants and distancing across studies. Authors' Conclusions: The findings from this review indicate that social distancing behaviours are more likely to be undertaken by people who are worried about COVID‐19 and who believe that social distancing is an effective way of avoiding COVID‐19. Physical distancing behaviours are more likely to be undertaken by those who believe that they can control physical distancing from others, who believe that physical distancing is the social norm and who have a positive attitude to engaging in this behaviour. It is important to understand how to strengthen these behavioural determinants to develop effective interventions to promote distancing behaviours in any potential future waves of COVID‐19, and other respiratory infections. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic, caused by the SARS‐CoV‐2 virus, has resulted in illness, deaths and societal disruption on a global scale. Societies have implemented various control measures to reduce transmission of the virus and mitigate its impact. Individual behavioural changes are crucial to the successful implementation of these measures. One commonly recommended measure to limit risk of infection is face covering. It is important to identify those factors that can predict the uptake and maintenance of face covering. Objectives: We aimed to identify and synthesise the evidence on malleable psychological and psychosocial factors that determine uptake and adherence to face covering aimed at reducing the risk of infection or transmission of COVID‐19. Search Methods: We searched various literature sources including electronic databases (Medline ALL, Child Development & Adolescent Studies, ERIC, PsycInfo, CINAHL & Web of Science), web searches, conference proceedings, government reports, other repositories of literature and grey literature. The search strategy was built around three concepts of interest including (1) context (terms relating to COVID19), (2) behaviour of interest and (3) terms related to psychological and psychosocial determinants of COVID Health‐Related Behaviours and adherence or compliance with face covering, to capture malleable determines. Searches capture studies up until October 2021. Selection Criteria: Eligibility criteria included observational studies (both retrospective and prospective) and experimental studies that measure and report malleable psychological and psychosocial determinants and handwashing at an individual level, amongst the general public. Screening was supported by the Cochrane Crowd. Studies titles and abstracts were screened against the eligibility criteria by three independent screeners. Following this, all potentially relevant studies were screened at full‐text level by the research team. All conflicts between screeners were resolved by discussion between the core research team. Data Collection and Analysis: All data extraction was managed in EPPI‐Reviewer software. All eligible studies, identified through full‐text screening were extracted by one author. We extracted data on study information, population, determinant, behaviour and effects. A second author checked data extraction on 20% of all included papers. All conflicts were discussed by the two authors until consensus was reached. We assessed methodological quality of all included studies using an adapted version of the Joanna Briggs Institute Quality appraisal tool for cross‐sectional studies. Main Results: Our initial searches yielded 23,587 results, of which 23 were included in this review. The included studies were cross‐sectional in design, came from nine countries and had a combined sample of 54,401 participants. The vast majority of studies had samples from the general public, with five of the studies focusing on specific samples. All included studies considered people over the age of 18. The quality of 10 of the studies was rated as unclear, 10 were rated as low, and 3 rated high risk of bias, predominately due to lack of reporting of recruitment, sample characteristics and methodology. Ten studies were included in the meta‐analysis and 16 in the narrative synthesis. Findings from the meta‐analysis indicated that knowledge of COVID‐19 (0.341, 95% confidence interval [CI] = 0.06, 0.530, I2 = 100%) was the malleable determinant most associated with face covering behaviour. Perceived susceptibility of COVID‐19 (r = 0.088, 95% CI = −0.004, 0.180, I2 = 80%) and COVID‐related worry and anxiety (r = 0.064, 95% CI = −0.066, 0.191, I2 = 93% had little to no effect on face covering behaviour. In the narrative synthesis, the strongest association was found between perceived benefits and effectiveness of behaviours and mask wearing behaviour. Authors' Conclusions: Understanding the effects of various malleable determinants on COVID‐related face covering can aid in the development and implementation of interventions and public health campaigns to promote face covering behaviour in potential new waves of COVID‐19 or other respiratory infections. Knowledge of COVID and perceived benefits of face coverings warrant further consideration in future research and policy. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic, caused by the SARS‐CoV‐2 virus, has resulted in illness, deaths and societal disruption on a global scale. Societies have implemented various control measures to reduce transmission of the virus and mitigate its impact. Individual behavioural changes are crucial to the successful implementation of these measures. One commonly recommended measure to limit risk of infection is frequent handwashing. It is important to identify those factors that can predict the uptake and maintenance of handwashing. Objectives: We aimed to identify and synthesise the evidence on malleable psychological and psychosocial factors that determine uptake and adherence to handwashing aimed at reducing the risk of infection or transmission of COVID‐19. Search Methods: We searched various literature sources including electronic databases (Medline ALL, Child Development & Adolescent Studies, ERIC, PsycInfo, CINAHL and Web of Science), web searches, conference proceedings, government reports, other repositories of literature and grey literature. The search strategy was built around three concepts of interest including (1) context (terms relating to COVID‐19), (2) behaviour of interest and (3) terms related to psychological and psychosocial determinants of COVID Health‐Related Behaviours and adherence or compliance with handwashing, to capture malleable determines. Searches capture studies up until October 2021. Selection Criteria: Eligibility criteria included observational studies (both retrospective and prospective) and experimental studies that measure and report malleable psychological and psychosocial determinants and handwashing at an individual level, amongst the general public. Screening was supported by the Cochrane Crowd. Titles and abstracts were screened against the eligibility criteria by three independent screeners. Following this, all potentially relevant studies were screened at full‐text level by the research team. All conflicts between screeners were resolved by discussion between the core research team. Data Collection and Analysis: All data extraction was managed in EPPI‐Reviewer software. All eligible studies, identified through full‐text screening were extracted by one author. We extracted data on study information, population, determinant, behaviour and effects. A second author checked data extraction on 20% of all included papers. All conflicts were discussed by the two authors until consensus was reached. We assessed methodological quality of all included studies using an adapted version of the Joanna Briggs Institute Quality appraisal tool for cross‐sectional studies. Main Results: Our initial searches yielded 23,587 results, of which 56 studies were included in this review. The included studies were cross sectional in design, came from 22 countries and had a combined sample of 199,376 participants. The vast majority of studies had samples from the general public, with eight of the studies focusing on specific samples. All included studies considered people over the age of 18. The quality of the majority of the studies was good (n = 30 rated low risk of bias), with 8 rated high risk of bias, predominately due to lack of reporting of recruitment, sample characteristics and methodology. Thirty‐four studies were included in the narrative synthesis and 28 in the meta‐analysis. Findings indicated that emotions about COVID‐19 (worry [0.381, confidence interval [CI] = 0.270–0.482, I2 = 92%) and anxiety (0.308, CI = 0.154–0.448, I2 = 91%]), knowledge of COVID‐19 (0.323, CI = 0.223–0.417, I2 = 94%), and perceived social norms (0.303, CI = 0.184–0.413, I2 = 92%) were among the malleable determinants most associated with handwashing. Perceived severity (0.006, CI = ‐0.011–0.023) and susceptibility of COVID‐19 (0.041, CI = −0.034 to 0.115) had little to no effect on handwashing behaviour. Authors' Conclusions: Understanding the effects of various malleable determinants on COVID‐related handwashing can aid in the development and implementation of interventions and public health campaigns to promote handwashing behaviour in potential new waves of COVID‐19 or other respiratory infections. Emotions about COVID, knowledge of COVID and perceived social norms warrant further consideration in future research and policy. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic, caused by the SARS‐CoV‐2 virus, has resulted in illness, deaths and societal disruption on a global scale. Societies have implemented various control measures to reduce transmission of the virus and mitigate its impact. Individual behavioural changes are crucial to the successful implementation of these measures. Common recommended measures to limit risk of infection include frequent handwashing, reducing the frequency of social interactions and the use of face coverings. It is important to identify those factors that can predict the uptake and maintenance of these protective behaviours. Objectives: We aimed to identify and map the existing evidence (published and unpublished) on psychological and psychosocial factors that determine uptake and adherence to behaviours aimed at reducing the risk of infection or transmission of COVID‐19. Search Methods: Our extensive search included electronic databases (n = 12), web searches, conference proceedings, government reports, other repositories including both published peer reviewed, pre‐prints and grey literature. The search strategy was built around three concepts of interest including (1) context (terms relating to COVID‐19), (2) behaviours of interest and (3) terms related to psychological and psychosocial determinants of COVID Health‐Related Behaviours and adherence or compliance with recommended behaviours, to capture both malleable and non‐malleable determinants (i.e. determinants that could be changed and those that could not). Selection Criteria: This Evidence and Gap Map (EGM) includes all types of studies examining determinants of common recommended behaviours aimed at mitigating human‐to‐human spread of COVID‐19. All potential malleable and non‐malleable determinants of one or more behaviours are included in the map. As part of the mapping process, categories are used to group determinants. The mapping categories were based on a previous rapid review by Hanratty 2021. These include: 'behaviour', 'cognition', 'demographics', 'disease', 'emotions', 'health status', 'information', 'intervention', and 'knowledge'. Those not suitable for categorisation in any of these groups are included in the map as 'other' determinants. Data Collection and Analysis: Results were imported to a bibliographic reference manager where duplications of identical studies gathered from multiple sources were removed. Data extraction procedures were managed in EPPI‐Reviewer software. Information on study type, population, behaviours measured and determinants measured were extracted. We appraised the methodological quality of systematic reviews with AMSTAR‐2. We did not appraise the quality of primary studies in this map. Main Results: As of 1 June 2022 the EGM includes 1034 records reporting on 860 cross‐sectional, 68 longitudinal, 78 qualitative, 25 reviews, 62 interventional, and 39 other studies (e.g., mixed‐methods approaches). The map includes studies that measured social distancing (n = 487), masks and face coverings (n = 382), handwashing (n = 308), physical distancing (n = 177), isolation/quarantine (n = 157), respiratory hygiene/etiquette (n = 75), cleaning surfaces (n = 59), and avoiding touching the T‐zone (n = 48). There were 333 studies that assessed composite measures of two or more behaviours. The largest cluster of determinants was 'demographics' (n = 730 studies), followed by 'cognition' (n = 496 studies) and determinants categorised as 'other' (n = 447). These included factors such as 'beliefs', 'culture' and 'access to resources'. Less evidence is available for some determinants such as 'interventions' (n = 99 studies), 'information' (n = 101 studies), and 'behaviour' (149 studies). Authors' Conclusions: This EGM provides a valuable resource for researchers, policy‐makers and the public to access the available evidence on the determinants of various COVID‐19 health‐related behaviours. The map can also be used to help guide research commissioning, by evidence synthesis teams and evidence intermediaries to inform policy during the ongoing pandemic and potential future outbreaks of COVID‐19 or other respiratory infections. Evidence included in the map will be explored further through a series of systematic reviews examining the strength of the associations between malleable determinants and the uptake and maintenance of individual protective behaviours. [ABSTRACT FROM AUTHOR]

Background: The free‐access (FA) intravenous alcohol self‐administration (IV‐ASA) paradigm is an experimental approach that can identify modulators of alcohol consumption in humans. Moreover, the outcome measures of IV‐ASA paradigms are associated with self‐reported alcohol intake using the timeline follow‐back method (TLFB). To evaluate how FA IV‐ASA reflects drinking in real life, we examined the relationship between an objective marker of recent alcohol intake, phosphatidylethanol in blood (B‐PEth), and TLFB and measures obtained during IV‐ASA in individuals with alcohol use disorder (AUD) and social drinkers (SD). We also explored the associations between these measures and gut‐brain peptides involved in AUD pathophysiology. Methods: Thirty‐eight participants completed a laboratory session in which they self‐administered alcohol intravenously. The safety limit was 200 mg%, and main outcomes were mean and peak breath alcohol concentrations (BrAC). Blood samples were drawn prior to IV‐ASA and subjective alcohol effects were rated during the experiment. Results: The study sample comprised 24 SD and 14 participants with DSM‐5 mild AUD. Although BrACs were not associated with B‐PEth or TLFB in the full sample or AUD subgroup, there was an association with TLFB in SD. In both subgroups, BrACs were associated with alcohol craving but with differential timing. Total ghrelin levels were higher in AUD participants than in SD. Conclusions: No associations between B‐PEth levels and achieved BrACs were observed in the mild AUD group, the SD group, or the full sample. The ability for FA IV‐ASA to reflect recent drinking was confirmed only for TLFB in SD, whereas there were no associations within the smaller subsample of participants with mild AUD or in the full sample. Further studies that include a larger AUD sample are warranted. The association of BrACs with craving for alcohol suggests that the IV‐ASA method may be useful for assessing interventions that target craving. This could be explored by using the FA IV‐ASA model to evaluate the effects on craving of approved pharmacotherapies for AUD. [ABSTRACT FROM AUTHOR]

Background: Understanding how blood alcohol concentrations (BAC) achieved after drinking are determined is critical to predicting alcohol exposure to the brain and other organs and alcohol's effects. However, predicting end‐organ exposures is challenging, as there is wide variation in BAC achieved after drinking a specified volume of alcohol. This variation is partly due to differences in body composition and alcohol elimination rates (AER), but there are limited data on how obesity affects AER. Here, we assess associations between obesity, fat‐free mass (FFM), and AER in women and examine whether bariatric surgeries, which are linked to an increased risk of alcohol misuse, affect these associations. Methods: We analyzed data from three studies that used similar intravenous alcohol clamping procedures to estimate AER in 143 women (21 to 64 years old) with a wide range of body mass index (BMI; 18.5 to 48.4 kg/m2). Body composition was measured in a subgroup using dual‐energy X‐ray absorptiometry (n = 42) or Bioimpedance (n = 60), and 19 of the women underwent bariatric surgery 2.1 ± 0.3 years before participation. We analyzed data using multiple linear regression analyses. Results: Obesity and older age were associated with a faster AER (BMI: rs = 0.70 and age: rs = 0.61, both p < 0.001). Compared to women with normal weight, AER was 52% faster (95% Confidence Interval: 42% to 61%) in women with obesity. However, BMI lost predictive value when adding fat‐free mass (FFM) to the regression model. Age, FFM, and its interaction explained 72% of individual variance in AER (F (4, 97) = 64.3, p < 0.001). AER was faster in women with higher FFM, particularly women in the top tertile of age. After controlling for FFM and age, bariatric surgery was not associated with differences in AER (p = 0.74). Conclusions: Obesity is associated with a faster AER, but this association is mediated by an obesity‐related increase in FFM, particularly in older women. Previous findings of a reduced alcohol clearance following bariatric surgery compared with prior to surgery are likely explained by a reduction in FFM post‐surgery. [ABSTRACT FROM AUTHOR]

The article responds to comments on a study about alcohol metabolism in individuals with obesity. It also discuss the impact of bariatric procedures on alcohol metabolism and the importance of accurate measurement techniques, especially for adolescents undergoing surgery. It suggests the implementation of regular alcohol screening as a means to address the heightened risk of alcohol-related complications in bariatric surgery patients.

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders. [ABSTRACT FROM AUTHOR]

This is the protocol for a Campbell systematic review. The objectives are as follows: we intend to identify and synthesise the existing evidence (published and unpublished) on malleable psychological and psychosocial factors that determine uptake and adherence to behaviours that can reduce the risk of infection or transmission of COVID-19. [ABSTRACT FROM AUTHOR]

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free‐access and progressive‐ratio, operant‐response human alcohol self‐administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age = 23.7, SD = 2.0; 45% female) of European descent who reported 12.6 drinking days (SD = 5.2) out of the previous 30 (average = 4.1 drinks per drinking day [SD = 1.7]). Individuals diverged in their alcohol self‐administration behavior, such that free‐access and progressive‐ratio paradigm outcomes were not significantly correlated (p = 0.44). Free‐access alcohol seeking was related to enjoying alcohol (p < 0.001), but not craving (p = 0.48), whereas progressive‐ratio seeking at similar levels of alcohol exposure was related to craving (p = 0.02), but not enjoying (p = 0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps > 0.70) to preferred level of breath alcohol concentration (BrAC) in the free‐access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps < 0.05) to alcohol seeking in the progressive‐ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self‐administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials. [ABSTRACT FROM AUTHOR]

Background: It is well established that even moderate levels of alcohol affect cognitive functions such as memory, self‐related information processing, and response inhibition. Nevertheless, the neural mechanisms underlying these alcohol‐induced changes are still unclear, especially on the network level. The default mode network (DMN) plays an important role in memory and self‐initiated mental activities; hence, studying functional interactions of the DMN may provide new insights into the neural mechanisms underlying alcohol‐related changes. Methods: We investigated resting‐state functional connectivity (rsFC) of the DMN in a cohort of 37 heavy drinkers at a breath alcohol concentration of 0.8 g/kg. Alcohol and saline were infused in a single‐blind crossover design. Results: Intranetwork connectivity analyses revealed that participants showed significantly decreased rsFC of the right hippocampus and right middle temporal gyrus during acute alcohol exposure. Moreover, follow‐up analyses revealed that these rsFC decreases were more pronounced in participants who reported stronger craving for alcohol. Exploratory internetwork connectivity analyses of the DMN with other resting‐state networks showed no significant alcohol‐induced changes, but suffered from low statistical power. Conclusions: Our results indicate that acute alcohol exposure affects rsFC within the DMN. Functionally, this finding may be associated with impairments in memory encoding and self‐referential processes commonly observed during alcohol intoxication. Future resting‐state functional magnetic resonance imaging studies might therefore also investigate memory function and test whether DMN‐related connectivity changes are associated with alcohol‐induced impairments or craving. [ABSTRACT FROM AUTHOR]

An emerging enabling technology for electronic holographic displays is the surface acoustic wave (SAW) acousto‐optical modulator family. The authors describe successful demonstration of a horizontal parallax only (HPO) electroholographic display composed of 10 edge‐emitting SAW modulators with 8 channels each. It features innovations in display architecture, modulator design, packaging, and illumination. [ABSTRACT FROM AUTHOR]

Background: The preference for immediate rewards and high sensation seeking are both potent risk factors for alcohol use disorder (AUD), but how they interact during intoxication is poorly understood. To model decision making linked to AUD risk, we tested heavy drinkers for impulsive choice (delay discounting with alcohol:money or money:money) and behavioral sensation seeking using a novel odor choice task. Laboratory tasks measured actual behavior with real contingencies. Our goals were to determine, in heavy drinkers, (i) alcohol's effects on delay discounting, and (ii) how AUD risk factors relate to delay discounting, and (iii) how delay discounting with alcohol choices compares with strictly monetary choices. Methods: Thirty‐five heavy drinkers (≥2 binges per month; age = 22.8 ± 2.2; 20 male; 5.8 ± 2.3 drinks/drinking day) performed cross‐commodity discounting (CCD) of immediate alcohol vs. delayed money, a monetary delay discounting (DD), and behavioral sensation‐seeking tasks. CCD and DD were performed while sober and during controlled alcohol infusion targeting 0.08 g/dl. The behavioral sensation‐seeking task presented binary choices of odorants varying in intensity and novelty, and the risk of exposure to a malodorant. Results: CCD and DD behaviors were highly correlated across conditions, mean r = 0.64. Alcohol increased delayed reward preference in DD, p = 0.001, but did not alter mean CCD, p > 0.16. However, alcohol‐induced changes in CCD correlated with behavioral sensation seeking, such that higher sensation seekers' immediate alcohol preference increased when intoxicated, p = 0.042; self‐reported sensation seeking was uncorrelated, ps > 0.08. Behavioral sensation seeking also correlated with "want" alcohol following a priming dose targeting 0.035 g/dl, p = 0.021. CCD and DD did not correlate with self‐reported drinking problems or other personality risk traits. Conclusions: Alcohol increased impulsive alcohol choice in high sensation seekers, suggesting an interaction that may underlie impaired control of drinking, at least in a subset of heavy drinkers—consistent with models highlighting high novelty/sensation‐seeking AUD subtypes. Discounting behavior overall appears to be a generalized process, and relatively stable across methods, repeated testing, and intoxication. These findings further support the utility of behavioral tasks in uncovering key behavioral phenotypes in AUD. [ABSTRACT FROM AUTHOR]

Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper was to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, "To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs." We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants' brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes. [ABSTRACT FROM AUTHOR]

Background: Individuals perceive the effects of alcohol differently, and the variation is commonly used in research assessing the risk for developing an alcohol use disorder. Such research is supported by both oral and intravenous (IV) alcohol administration techniques, and any differences attributable to the route employed should be understood. Our objective was to test whether an individual's subjective responses to alcohol are similar when the breath alcohol concentration (BrAC) trajectory resulting from oral administration is matched by IV administration. Methods: We conducted a 2‐session, within‐subject study in 44 young adult, healthy, nondependent drinkers (22 females and 22 males). In the first session, subjects ingested a dose of alcohol which was individually calculated, on the basis of total body water, to yield a peak BrAC near 80 mg/dl, and the resulting BrAC trajectory was recorded. A few days later, subjects received an IV alcohol infusion rate profile, precomputed to replicate each individual's oral alcohol BrAC trajectory. In both sessions, we assessed 4 subjective responses to alcohol: SEDATION, SIMULATION, INTOXICATION, and HIGH; at baseline and frequently for 4 hours. We compared the individuals' baseline‐corrected responses at peak BrAC and at half‐peak BrAC on both the ascending and descending limbs. We also computed and compared Pearson‐product moment correlations of responses by route of administration, the Mellanby measure of acute adaptation to alcohol, and the area under the entire response curve for each subjective response. Results: No significant differences in any measure could be attributed to the route of alcohol administration. Eleven of 12 response comparisons were significantly correlated across the routes of alcohol administration, with 9 surviving correction for multiple measures, as did the Mellanby effect and area under the response curve correlations. Conclusions: The route of alcohol administration has a minimal effect on subjective responses to alcohol when an individual's BrAC exposure profiles are similar. Individuals perceive the effects of alcohol differently, and the variation is used in both oral and intravenous alcohol research assessing the alcohol use disorder risk. Any differences attributable to the route of administration should be understood. Subjective responses obtained during an oral alcohol challenge were compared to those obtained during a subsequent intravenous alcohol challenge replicating the oral alcohol exposure trajectory. The route of alcohol administration has a minimal effect on subjective responses when an individual's exposure profiles are similar. [ABSTRACT FROM AUTHOR]

Background: Studies in animal models document that forced abstinence from usual consumption of alcohol changes subsequent seeking and consumption, with increases or decreases depending on the species, duration of abstinence, number of deprivations, and sex. Human laboratory‐based alcohol deprivation studies are rare. Methods: We conducted a 2‐session, within‐participant, randomized‐order comparison of intravenous, progressive ratio, alcohol self‐administration during 2.5 hours of progressive work for alcohol and/or vehicle; once while the participants pursued their usual drinking habits and once after 2 weeks of closely monitored, voluntary outpatient abstinence from alcohol. The schedule of work for rewards and the incremental increases in breath alcohol concentration following completion of an alcohol work‐set were identical across participants. Fifty young‐adult (27 men), heavy‐drinking participants completed both sessions. Our primary hypothesis was that motivation to work for alcohol after 2 weeks of abstinence would be greater in participants with a weekly binge pattern of drinking, compared to those who regularly drink heavily, and we intended to explore associations with biological family history of alcoholism and sex. Results: We detected no change in work for alcohol associated with recent drinking history. However, females, on average, increased their work for alcohol upon resumption after 2 weeks of abstinence (mean ± SEM = +16.3 ± 9.6%), while males decreased that work (−24.8 ± 13.8%). The sex difference was substantial and significant (p < 0.03), with a medium effect size (Cohen's d = 0.63). Conclusions: We believe a more comprehensive study of mechanisms underlying the sex differences in the human postabstinence response is warranted. [ABSTRACT FROM AUTHOR]

Background Adolescence is a critical period for the development of alcohol use disorders; drinking habits are rather unstable and genetic influences, such as male sex and a positive family history of alcoholism ( FH), are often masked by environmental factors such as peer pressure. Methods We investigated how sex and FH modulate alcohol use in a sample of 18- to 19-year-olds from the Dresden Longitudinal Study on Alcohol use in Young Adults. Adolescents reported their real-life drinking in a TimeLine Follow-Back interview. They subsequently completed a training and an experimental session of free-access intravenous alcohol self-administration (i.v. ASA) using the computer-assisted alcohol infusion system to control for environmental cues as well as for biological differences in alcohol pharmacokinetics. During i.v. ASA, we assessed subjective alcohol effects at 8 time points. Results Women reported significantly less real-life drinking than men and achieved significantly lower mean arterial blood alcohol concentrations (a BACs) in the laboratory. At the same time, women reported greater sedation relative to men and rated negative effects as high as did men. A positive FH was associated with lower real-life drinking in men but not in women. In the laboratory, FH was not linked to i.v. ASA. Greater real-life drinking was significantly positively associated with higher mean a BACs in the laboratory, and all i.v. ASA indices were highly correlated across the 2 sessions. Conclusions We conclude that adolescent women chose lower a BACs because they experienced adverse alcohol effects, namely sedation and negative effects, at lower a BACs than men. A positive FH was not apparent as risk factor for drinking in our young sample. The i.v. ASA method demonstrated good external validity as well as test-retest reliability, the latter indicating that a separate training session is not required when employing the i.v. ASA paradigm. [ABSTRACT FROM AUTHOR]

Background Although negative mood has long been implicated in differences in alcohol seeking by men and women, little research has used precise, well-controlled laboratory experiments to examine how negative mood affects alcohol-seeking behaviors. Methods A total of 34 (19 women) community-dwelling, alcohol-using adults aged 21 to 32 (mean age = 24.86, SD = 3.40, 74.3% Caucasian; Alcohol Use Disorders Identification Test [AUDIT] = 10.1, SD = 3.4) completed 2 counterbalanced intravenous alcohol self-administration sessions: one under negative mood and one under neutral mood. Fourteen individuals (9 women; mean age = 25.00, SD = 2.77) participated in an alcohol 'liking' experiment (i.e., free access [FA] drinking) and 20 individuals (10 women; mean age = 24.77, SD = 3.73) participated in an alcohol 'wanting' experiment, in which gaining access to alcohol required progressively effortful work. There was no significant difference between men and women on the AUDIT, t(32) = −0.38, p = 0.71. Results Priming with negative mood induction caused a significant decrease in self-reported mood (mean change = −1.85, t(32) = −6.81, p < 0.001), as intended. In FA, negative mood was associated with a significantly increased peak breath alcohol concentration (BrAC; F = 9.41, p = 0.01), with a trend toward a greater effect in men than in women ( F = 2.67, p = 0.13). Negative mood also had a significant effect on peak BrAC achieved in the progressive work paradigm ( F = 5.28, p = 0.04), with a significantly stronger effect in men ( F = 5.35, p = 0.03) than women; men also trended toward more consistent work for alcohol across both neutral and negative sessions. Conclusions These preliminary findings demonstrate a gender-specific response on how mood affects alcohol seeking and suggest gender-specific interventions to prevent mood-based alcohol consumption. [ABSTRACT FROM AUTHOR]

Background Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. Methods One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol 'clamp,' during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism ( SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. Results Recent drinking history ( p = 0.01), and recent drinking history × genotype interaction ( p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. Conclusions Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol. [ABSTRACT FROM AUTHOR]

Objective Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. Methods BOLD activation to food aromas in non-obese women ( n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. Results BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. Conclusions An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon. [ABSTRACT FROM AUTHOR]

Background Construct interview that correctly identifies those with alcohol use disorder have limitation, especially when the subjects are motivated to minimize the magnitude of drinking behavior. Current laboratory tests to detect excessive alcohol consumption are limited by marginal sensitivity/specificity. Excessive drinking has been shown to affect several organ systems, which may be reflected in changes in quantity of plasma proteins. Our aim was to employ novel proteomic analyses to identify potential markers for excessive alcohol use. Methods A prospective case-control study included 49 controls and 54 excessive drinkers (discovery cohort). The serum proteomic analyses in these subjects were performed, and the results were tested in the verification cohort (40 controls and 40 excessive drinkers). Results Using the appropriate cutoff and confirmation with ELISA, we identified 4 proteins which were significantly elevated in the serum of excessive drinkers: AT-rich interactive domain-containing protein 4B (ARID4B), phosphatidylcholine-sterol acyltransferase (LCAT), hepatocyte growth factor-like protein (MST1), and ADP-ribosylation factor 6 (ARL6). The performance of the conventional markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], percentage of carbohydrate-deficient transferrin [%CDT], and mean corpuscular volume [MCV]) discriminating between excessive alcohol use and controls had an area under the curve (AUC) ranging from 0.21 (ALT) to 0.67 (MCV). The AUC of these novel proteins showed the improvement in the detection of excessive drinkers compared to conventional laboratory tests, ranging from 0.73 (for ARID4B) to 0.86 (for ARL6). Conclusions We have identified 4 novel proteins that can discern subjects with excessive alcohol use. Further studies are needed to determine the clinical implications of these markers to detect excessive alcohol use and confirm abstinence. [ABSTRACT FROM AUTHOR]

Background Operant responding paradigms quantify a subject's motivation for reward, but such studies employing ingested alcohol cannot assure the same incremental increase in brain exposure to alcohol across subjects because of substantial variability in absorption kinetics. We developed a human progressive ratio ( PR) paradigm using the computer-assisted self-infusion of ethanol ( CASE) system that overcomes such variability and conducted a pilot study to assess its utility for detecting an interaction of subjects' GABRA2 or GABRG1 genotype and pretreatment with 1 mg of lorazepam ( LZ) vs. placebo on their willingness to work for alcohol rewards. Methods Twenty healthy, nondependent drinkers, aged 21 to 27, were balanced on rs279871 and rs2350439 single nucleotide polymorphisms in the GABRA2 and GABRG1 genes, respectively. Subjects worked for alcohol, with water as an alternative reinforcer (AR), using a progressive schedule of a task that required constant attention and adapted to both fatigue and drug effects. Testing began 1 hour after pretreatment with 1 mg LZ or placebo in a crossover design. Results The CASE system performed well, and the constant attention task was perceived as work by all subjects. GABRA2 homozygosity did not significantly predict either breakpoint or cumulative work, whereas a significant GABRG1 genotype by LZ pretreatment interaction for cumulative work was detected ( p = 0.04). Breakpoint revealed a weak trend toward pretreatment drug effects ( p = 0.11), and a somewhat stronger interaction of LZ pretreatment with GABRG1 genotype ( p = 0.06). GABRG1 status revealed a more complex relationship with respect to motivation for alcohol with and without LZ pretreatment; AG and GG individuals worked more for alcohol under both pretreatment conditions, while AA individuals worked more for the AR. Conclusions The CASE PR paradigm shows promise as a laboratory method for use in drug development and phenotyping studies. [ABSTRACT FROM AUTHOR]

Background The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration ( BrAC) acting alone. To test this proposition, a 2-session experiment was designed in which carefully prescribed, constant-slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design. Methods Individualized intravenous infusion rate profiles of 6% ethanol (EtOH) that achieved the constant-slope trajectories for an individual were precomputed using a physiologically based pharmacokinetic model. Adjusting the parameters of the model allowed each infusion profile to account for the subject's EtOH distribution and elimination kinetics. Sessions were conducted in randomized order and made no use of feedback of BrAC measurements obtained during the session to modify the precalculated infusion profiles. In one session, an individual's time course of exposure, BrAC( t), was prescribed to rise at a constant rate of 6.0 mg% per minute until it reached 68 mg% and then descend at −1.0 mg% per minute; in the other, to rise at a rate of 3.0 mg% per minute. The 2 exposure trajectories were designed to intersect at a BrAC ( t = 20 minutes) = 60 mg% at an experimental time of 20 minutes. Results Intersection points for 54 of 61 subjects were within prescribed deviations (range of ±3 mg% and ±4 minutes from the nominal intersection point). Conclusions Results confirmed the feasibility of applying the novel methods for achieving the intended time courses of the BrAC, with technical problems limiting success to 90% of the individuals tested. [ABSTRACT FROM AUTHOR]

Background: The differentiator model predicts that individuals with a positive family history of alcoholism (FHA) or heavy alcohol consumers will feel more sensitive to the effects of alcohol on the ascending phase of the blood alcohol content while feeling less sedated on the descending phase. This study tested whether subjective perceptions are sensitive to the slope of breath alcohol concentration (BrAC) and whether that sensitivity is associated with an FHA and/or recent drinking history (RDH). Methods: Family-history-positive (FHP, n = 27) and family-history-negative (FHN, n = 27) young adult nondependent drinkers were infused intravenously with alcohol in 2 sessions separated by 1 week. After 20 minutes, one session had an ascending BrAC (+3.0 mg%/min), while the other session had a descending BrAC (−1 mg%/min). The BrAC for both sessions at this point was approximately 60 mg%, referred to as the crossover point. Subjective perceptions of intoxication, high, stimulated, and sedation were sampled frequently and then interpolated to the crossover point. Within-subject differences between ascending and descending responses were examined for associations with FHA and/or RDH. Results: Recent moderate drinkers reported increased perceptions of feeling intoxicated ( p < 0.023) and high ( p < 0.023) on the ascending slope compared with the descending slope. In contrast, recent light drinkers felt more intoxicated and high on the descending slope. Conclusions: Subjective perceptions in young adult social drinkers depend on the slope of the BrAC when examined in association with RDH. These results support the differentiator model hypothesis concerning the ascending slope and suggest that moderate alcohol consumers could be at risk for increased alcohol consumption because they feel more intoxicated and high on the ascending slope. Subjects did not feel less sedated on the descending slope, contrary to the differentiator model but replicating several previous studies. [ABSTRACT FROM AUTHOR]

Background: The biological mechanisms by which acute stress increases alcohol consumption are unclear. One potential mechanism is that stress acts by altering the pharmacological and subjective effects of alcohol. Acute stress produces a cascade of physiological and psychological effects, each with a distinctive time course. In this study, we investigated whether different phases of response to an acute stress alter the subjective effects of intravenous alcohol, by administering the drug at 2 different times after the stress. Methods: Healthy men ( n = 25) participated in 2 sessions: 1 with the Trier Social Stress Test and the other with a nonstressful control task, each followed by infusions of intravenous alcohol (targeting 40 mg% in 5 minutes) and placebo. One group of participants received alcohol within 1 minute of completing the tasks (Alc0, n = 11), followed by placebo 30 minutes later. In the other group (Alc30, n = 14), the order of alcohol and placebo infusions was reversed. Subjective effects (i.e., anxiety, stimulation, want more) and physiological measures (heart rate, blood pressure, salivary cortisol) were measured before and at repeated intervals after the tasks and infusions. Results: Stress did not change the subjective effects of alcohol in either group. However, when individual differences in alcohol responses were considered, stress differentially altered the stimulant-like and sedative effects of alcohol. Among individuals who exhibited predominantly stimulant responses to alcohol in the nonstressful condition, stress decreased the stimulant-like effects of alcohol and 'wanting more.' By contrast, among participants who did not report stimulation after alcohol in the control session, stress decreased the sedative effects and increased 'want more.' In addition, alcohol administered immediately after the Trier Social Stress Test dampened cortisol responses yet prolonged negative subjective responses to the stress. Conclusions: These findings demonstrate that there are bidirectional relationships between alcohol and stress. Alcohol influences responses to stress, and stress changes reactions to alcohol, depending on an individual's pattern of response to alcohol. This study highlights the fact that stress-alcohol interactions vary among individual drinkers, suggesting that the effects of stress on motivation to drink alcohol may also differ between individuals. [ABSTRACT FROM AUTHOR]

The article presents the conducted study to determine the test-retest variability (TRV) of [11C]raclopride- (RAC) binding in nontreatment seeking alcoholics (NSA). The methods used in the study include the multilinear reference tissue method (MRTM), single-bolus RAC positron emission tomography (PET) and Logan graphical analysis (LGA). Results of the study showed that baseline striatal RAC binding is very reproducible in NTS subjects.

Significant evidence has accumulated to suggest an association between single-nucleotide polymorphisms (SNPs) in the GABRA2 gene and alcoholism. However, research has yet to show an association between these polymorphisms and the human brain's reward system function. In this study, we stratified subjects who had participated in an fMRI study of alcohol cue responses according to their genotype at a SNP in GABRA2 (rs279871) shown to be associated with alcohol dependence (). Genotyping showed 13 subjects to be homozygous for the high-risk allele (AA), and 23 subjects to be heterozygous (AG). In fMRI, subjects were exposed to the aromas of their preferred alcoholic drink odors (AO), as well as to appetitive control odors (ApCO) under both alcohol intoxication and placebo control conditions. Homozygous AA subjects had a larger [AO > ApCO] response than did AG subjects in medial frontal cortical areas thought to code reward value. However, AG subjects had a larger [AO > ApCO] effect in the ventral tegmental area. Alcohol intoxication did not alter these group differences. These are the first data to suggest that GABRA2 genotype could affect the brain's responses to cues associated with alcohol. [ABSTRACT FROM AUTHOR]

Obesity, smoking, and conduct problems have all been associated with decrements in brain function. However, their additive and interactive effects have rarely been examined. To address the deficiency, we studied P300a and P300b electroencephalographic potentials in 218 women grouped by the presence versus absence of: (1) a BMI ≥ 30 kg/m2; (2) recent smoking; and (3) ≥ 2 childhood conduct problems. Analyses revealed smaller P300a and P300b amplitudes over the posterior scalp among recent smokers versus nonsmokers. No corresponding group differences were found in P300 latencies or frontal scalp amplitudes. The most interesting analysis result was an interaction between conduct problems and obesity limited to the frontally generated P300a component: its latency was significantly greater in women with both attributes than in those with either or neither attribute. An exploratory ANOVA, substituting the genotype of a GABRA2 SNP for conduct problems, also demonstrated an interaction with obesity affecting P300a latency. It is hypothesized that conduct problems, and a conduct-problem-associated GABRA2 genotype, decrease the age-of-onset and/or increase the lifetime duration of obesity. As a result, they may potentiate the adverse effects of obesity on frontal white matter and thereby increase P300a latency. Smoking may affect brain function by a different mechanism to reduce posterior scalp P300a and P300b amplitudes while preserving frontal scalp P300a latency and amplitude. (Am J Addict 2010;00:1-10) [ABSTRACT FROM AUTHOR]

Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 ( CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis. Methods: We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons. Results: Significant associations ( p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene. Conclusions: Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: While there is extensive literature on the relationship between the P3 component of event-related potentials (ERPs) and risk for alcoholism, there are few published studies regarding other potentially important ERP components. One important candidate is the N4(00) component in the context of semantic processing, as abnormalities in this component have been reported for adult alcoholics. Method: A semantic priming task was administered to nonalcohol dependent male offspring (18 to 25 years) of alcoholic fathers [high risk (HR) n = 23] and nonalcoholic fathers [low risk (LR) n = 28] to study whether the 2 groups differ in terms of the N4 component. Subjects were presented with 150 words and 150 nonwords. Among the words, 50 words (primed) were preceded by their antonyms (prime, n = 50), whereas the remaining 50 words were unprimed. For the analysis, N4 amplitude and latency as well as behavioral measures for the primed and unprimed words were considered. Results: A significant interaction effect was observed between semantic condition and group, where HR subjects did not show N4 attenuation for primed stimuli. Conclusion: The lack of N4 attenuation to primed stimuli and/or inability to differentiate between primed and unprimed stimuli, without latency and reaction time being affected, suggest deficits in semantic priming, especially in semantic expectancy and/or postlexical semantic processing in HR male offspring. Further, it indicates that it might be an electrophysiological endophenotype that reflects genetic vulnerability to develop alcoholism. [ABSTRACT FROM AUTHOR]

Background: Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. Methods: This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual’s physiology. The peak BrACs (Cmax), times of peak BrAC (Tmax), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. Results: The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean Cmax, Tmax, and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in Cmax and AUC were both 11%, while the mean %difference for Tmax was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. Conclusions: Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response. [ABSTRACT FROM AUTHOR]

Background: The mesolimbic dopamine (DA) system is implicated in the development and maintenance of alcohol drinking; however, the exact mechanisms by which DA regulates human alcohol consumption are unclear. This study assessed the distinct effects of alcohol-related cues and alcohol administration on striatal DA release in healthy humans. Methods: Subjects underwent 3 PET scans with [11C]raclopride (RAC). Subjects were informed that they would receive either an IV Ringer's lactate infusion or an alcohol (EtOH) infusion during scanning, with naturalistic visual and olfactory cues indicating which infusion would occur. Scans were acquired in the following sequence: (1) Baseline Scan: Neutral cues predicting a Ringer’s lactate infusion, (2) CUES Scan: Alcohol-related cues predicting alcohol infusion in a Ringer’s lactate solution, but with alcohol infusion after scanning to isolate the effects of cues, and (3) EtOH Scan: Neutral cues predicting Ringer's, but with alcohol infusion during scanning (to isolate the effects of alcohol without confounding expectation or craving). Results: Relative to baseline, striatal DA concentration decreased during CUES, but increased during EtOH. Conclusion: While the results appear inconsistent with some animal experiments showing dopaminergic responses to alcohol’s conditioned cues, they can be understood in the context of the hypothesized role of the striatum in reward prediction error, and of animal studies showing that midbrain dopamine neurons decrease and increase firing rates during negative and positive prediction errors, respectively. We believe that our data are the first in humans to demonstrate such changes in striatal DA during reward prediction error. [ABSTRACT FROM AUTHOR]

Background: Small, priming doses of alcohol enhance desire to drink, and thus play a role in the loss of control of alcohol consumption. Using functional magnetic resonance imaging (fMRI), we previously showed that alcoholic drink odors (AO; subjects’ drinks of choice) induce greater nucleus accumbens (NAc) activity than non-appetitive odors (NApO; grass, leather) in subjects at risk for alcoholism. Here we hypothesized that priming exposure to alcohol would enhance responses to AO in the NAc and orbitofrontal cortex in comparison to NApO (grass, leather) and to the appetitive control odors (ApCO) of chocolate and grape. Methods: Ten hazardous drinkers (mean age = 22.7; SD = 2.9, average drinks per drinking day = 5.9, SD = 2.3; drinking days/90 days = 50.4, SD = 13.7) were scanned on a 1.5T GE Signa MR scanner during intravenous infusion of lactated Ringer’s or 6% ethanol in lactated Ringer’s that was pharmacokinetically modeled to achieve a constant breath alcohol concentration (BrAC) of 50 mg% throughout imaging. During scanning, subjects sniffed AO, NApO, and ApCO. Results: Alcohol infusion enhanced the contrast between AO and NApO in the NAc, and in orbitofrontal, medial frontal, and precuneus/posterior cingulate regions. The contrast between AO and appetitive control odors (ApCO; chocolate and grape) was similarly larger in the orbital, medial frontal, precuneus, and posterior cingulate/retrosplenial areas, with the most robust finding being a potentiated response in the posterior cingulate/retrosplenial area. The orbital region is similar to an area previously shown to manifest satiety-related decreases in activity induced by food cues. Conclusions: The results suggest that priming exposure to alcohol renders a limbic network more responsive to alcohol cues, potentially enhancing desire to drink. [ABSTRACT FROM AUTHOR]

Background: Human alcohol self-administration studies employing oral intake are subject to high variability of the resulting blood alcohol concentrations because of idiosyncrasies of gastrointestinal absorption kinetics among subjects. We sought to improve the subjects’ opportunity to control their brain alcohol exposure by computer-assisted i.v. self-administration. Methods: Instead of drinking, subjects could request increments of their arterial blood alcohol concentration (aBAC) of precisely 7.5 mg% at any time they wanted by pressing a button, provided their aBAC would not exceed 100 mg%. The latency between pushing the button and reaching the new aBAC peak was preset to be 2.5 minutes on the first day and was randomly changed to 1.5 or 3.5 minutes on days 2 and 3 in a crossover design. The necessary rate and amount of alcohol infusion was calculated by the software about once every second. Nine healthy social drinkers (4 females/5 males; mean age 25.0 ± 4.0 year) participated in 3 sessions each. Outcome measures were mean and maximum observed aBAC, and the number of alcohol requests. Results: Maximum aBAC was 76.5 ± 26.3 mg% on average over all experiments. When grouping days 2 and 3 according to latency (1.5 vs. 3.5 minutes), maximum aBAC and the number of requests in the session were significantly higher with the faster rise and all 3 outcome measures were significantly correlated between days. No such correlations were found between the first and either of the following days. Conclusions: These data suggest that CASE is practical and safe, and results in considerable alcohol exposure that can be manipulated with parameters chosen for the incremental exposure. Following 1 practice day, test–retest stability was good, suggesting a potential for use in scientific studies. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to determine time-course changes in in vivo ethanol (EtOH) concentrations using a novel subcutaneous (s.c.) microdialysis sampling technique. The hypothesis to be tested was that EtOH concentrations in the s.c. fluid would reflect blood EtOH concentrations. If this is the case, then s.c. microdialysis could allow a more detailed analysis of changes in in vivo levels of EtOH under different drinking paradigms. Methods: Adult male and female Wistar rats and male alcohol-preferring (P) rats were used in this study. A loop-style microdialysis probe was designed for s.c. applications. After initial in vitro characterization, probes were implanted under the skin between the shoulder blades. Animals were allowed to recover 4 to 24 hours prior to microdialysis collection (2.0 μl/min flow rate with isotonic saline). In vivo microdialysis experiments were then conducted to determine (i) the extraction fraction (or clearance) using EtOH no-net-flux (NNF) coupled with the alcohol clamp method, (ii) the dose–response and time-course effects after systemic EtOH administration and to compare with blood EtOH levels, and (iii) the time-course changes in EtOH levels during and after an EtOH drinking episode. Results: In vivo probe recovery (extraction fraction) obtained using the alcohol clamp method was 69 ± 3%, and was comparable to the in vitro recovery of 73 ± 2%. For the EtOH dose–response experiment, rats injected i.p. with 0.5, 1.0, or 2.0 g/kg EtOH showed a clear dose–response effect in the s.c. dialysate samples. Peak concentrations (70, 123, and 203 mg%, respectively) were reached by 15 minutes after injection. In an experiment comparing levels of EtOH in s.c. dialysis and arterial blood samples in rats administered 1.0 g/kg EtOH, similar time-course changes in in vivo EtOH concentrations were observed with both i.g. and i.p. EtOH administration. In P rats drinking 15% EtOH during a 1-hour scheduled access period, EtOH levels in s.c. microdialysates rose rapidly over the session and peaked at approximately 50 mg% at 60 to 80 minutes. Conclusions: Overall, these experiments indicate that s.c. EtOH and blood EtOH concentrations follow a similar time course. Moreover, s.c. microdialysis can be useful as an experimental approach for determining detailed time-course changes in in vivo EtOH concentrations associated with alcohol drinking episodes. [ABSTRACT FROM AUTHOR]

Background: A dopaminergic response to alcohol in humans has not been demonstrated consistently with positron emission tomography (PET). We hypothesized that the effect of alcohol on striatal dopamine (DA) release may be anatomically heterogeneous between subjects. Our approach was to identify voxels that exhibited alcohol-induced DA responses within the striatum, and to determine the relationships between DA responses and alcohol-related behavior. Methods: A novel method was developed to examine the anatomic extent and magnitude of striatal DA responses to alcohol across subjects. Thirteen healthy control subjects underwent 2 PET scans with [11C]raclopride (1 at baseline, 1 with an IV alcohol infusion to a target breath alcohol concentration of either 60 or 80 mg%). Parametric images of striatal binding potential (BP) were used to create maps of change in BP (ΔBP, an index of changes in DA levels). The anatomic extent and magnitude of DA responses were determined with voxel extraction methods. Subjective responses (“High,”“Intoxication”) to the alcohol infusion and behavioral data from the 90-day time-line follow back were assessed for relationships with DA responses to alcohol. Results: A voxel-wise t-test between baseline and alcohol BP images did not show any differences in D2/D3 receptor availability between the conditions. Data from the striatal ΔBP maps nevertheless showed that the anatomic extent and magnitude of alcohol-induced DA release in the striatum are correlated with subjective responses to alcohol. Conclusions: The heterogeneity of dopaminergic responses to alcohol across subjects may be a reason for the lack of reports demonstrating DA involvement in alcohol-related behaviors. By allowing for different spatial patterns of DA release within each subject's striata, we showed correlations between alcohol-induced DA release in the striata and behavioral outcomes related to alcohol. [ABSTRACT FROM AUTHOR]

Background: Electroencephalographic (EEG) measures of hemispheric asymmetry in anterior brain activity have been related to a variety of indices of psychopathology and emotionality. However, little is known about patterns of frontal asymmetry in alcohol-dependent (AD) samples. It is also unclear whether psychiatric comorbidity in AD subjects accounts for additional variance in frontal asymmetry, beyond a diagnosis of AD alone. Methods: We compared 193 AD subjects with 108 control subjects on resting brain activity in anterior and posterior regions, as indexed by asymmetries in α band power in the left and right hemispheres. Within the AD group alone, we examined whether comorbid major depressive disorder (MDD) or antisocial personality disorder (ASPD) had effects on regional asymmetry. Results: Compared with control subjects, AD subjects exhibited lower left, relative to right, cortical activation in anterior regions. Evidence that comorbidity in AD subjects accounted for further variance in EEG asymmetry was mixed; AD subjects with comorbid ASPD were not significantly different from those without ASPD, while AD subjects with a lifetime history of MDD showed less asymmetry in anterior regions than those without MDD. Conclusions: Our findings indicate that AD subjects exhibit a pattern of frontal asymmetry similar to that found in other psychiatric groups. Results examining the effects of comorbidity in AD on EEG asymmetry were inconclusive. The implications of our findings for future work are described. [ABSTRACT FROM AUTHOR]

This article summarizes the proceedings of a symposium organized and cochaired by Vijay Ramchandani and Sean O'Connor and presented at the 2004 Research Society on Alcoholism meeting in Vancouver, BC, Canada. The objectives of this symposium were: (1) to provide a rationale for the development and use of the alcohol clamp and the requirements for its use in alcohol challenge studies; (2) to highlight recent studies conducted using the alcohol clamp to identify sources of variation in the pharmacokinetics and pharmacodynamics of alcohol, as well as to address important research questions related to the relationship between the response to alcohol and the risk for alcoholism; and (3) to provide a perspective on progress, address limitations of the clamp, and identify new directions for alcohol challenge research. The symposium began with an introduction and overview of the alcohol clamp, by Vijay Ramchandani. This was followed by 4 presentations that highlighted recent studies conducted using the clamp including: (1) determination of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in a male Jewish population, by Yehuda Neumark; (2) examination of family history of alcoholism, recent drinking history, and levels and rates of administration as determinants of the response to alcohol and risk for alcoholism, by Sean O'Connor; (3) evaluation of the time course of ethanol intoxication on neuroendocrine function in humans, by Ulrich Zimmermann; and (4) a study of the effects of steady-state blood alcohol levels on auditory event-related potentials in rats, by Sandra Morzorati. Harriet de Wit summarized and discussed the research presented at the symposium and provided her perspective on future directions for research using the alcohol clamp. [ABSTRACT FROM AUTHOR]

Objective To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol. Method Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history-positive) and 49 controls (family history-negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance. Results The family history-positive and family history-negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions ( p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased ( p= 0.0001) and slowed the execution of saccades such that peak velocities decreased ( p= 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed ( p= 0.1). Latency of AS saccades demonstrated a significant overall FHA effect ( p= 0.02) and a significant interaction between FHA and response to alcohol over time ( p= 0.02). Conclusions Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml. [ABSTRACT FROM AUTHOR]

This manuscript represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Ting-Kai Li. The presentations were: (1) Introduction to the Symposium, by Ting-Kai Li; (2) ALDH2 polymorphism and alcohol metabolism, by Shih-Jiun Yin; (3) ALDH2 promoter polymorphism and alcohol metabolism, by David W. Crabb; (4) Use of BrAC clamping to estimate alcohol elimination rates: Application to studies of the influence of genetic and environmental determinants, by Sean O'Connor; and (5) Effect of food and food composition on alcohol elimination rates as determined by clamping, by Vijay A. Ramchandani. [ABSTRACT FROM AUTHOR]

Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (iv) infusion of an ethanol solution at a rate that is intermittently adjusted based on real-time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The 'quick-clamping' method replaced the oral loading dose with a preprogrammed infusion rate profile. A three-compartment physiologically-based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion-rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two-session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/iv method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean ± SE for quick-clamp: 17 ± 4 min; for oral/iv clamp: 45 ± 7 min). The quick-clamping method enables, for the first time, the examination of the early-phase neuroadaptive responses to alcohol in human subjects. [ABSTRACT FROM AUTHOR]

Event-related potentials (ERPs) were recorded from 83, 21- to 25-year-old nonalcoholic men varying in alcoholism vulnerability due to the presence/absence of an alcoholic family history or a personal history of antisocial personality disorder. ERPs were elicited by a visual oddball task in which the target was presented more frequently than the nontarget, in order to elicit impulsive or perseverative responding. Analyses of N200 and P300 revealed no group differences in the nontarget response. However, analyses of the target response revealed a significantly smaller P300 in the antisocial personality (ASP)+ group compared with the ASP- group. The P300 decrement was limited to frontal electrode sites and is interpreted as indicating the presence of subtle anterior brain dysfunction among ASP+ subjects. [ABSTRACT FROM AUTHOR]

The P3(00) event-related potential (ERP) was elicited in 80 normal, right-handed male subjects using a simple visual discrimination task, with electroencephalographic (EEG) activity recorded at 19 electrodes. P3 amplitude was larger over the right than over the left hemisphere electrode sites primarily at anteromedial locations (F3/4, C3/4) for target, novel, and standard stimuli. The N1, P2, and N2 components also demonstrated hemispheric asymmetries. The strongest P3 hemispheric asymmetries for all stimuli were observed at anterior locations, suggesting a frontal right hemisphere localization for initial stimulus processing, although target stimuli produced larger P3 amplitudes at parietal locations than did novel stimuli. The relationships of hemispheric asymmetries to anatomical variables, background EEG activity, and neurocognitive factors are discussed. [ABSTRACT FROM AUTHOR]

Background Propofol and remifentanil can be combined to deliver total intravenous anesthesia ( TIVA). Propofol and remifentanil are sometimes mixed in the same syringe. Since remifentanil is a solution and propofol is an emulsion, we hypothesized that they would separate over time when mixed in the same syringe. Methods Nine 60-ml polypropylene syringes were prepared as follows: Group A: 1.25 ml of remifentanil solution (1 mg·ml−1) was added to 48.75 ml of propofol (10 mg·ml−1) in three syringes. Group B: 2.5 ml of remifentanil (1 mg·ml−1) was added to 47.5 ml of propofol (10 mg·ml−1) in three syringes. Group C: 5 ml of remifentanil (1 mg·ml−1) was added to 45 ml of propofol (10 mg·ml−1) in three syringes. The remifentanil lyophilized powder was reconstituted with sterile water and added to the propofol by injection through the port on the bottom of the syringe. The syringe was then inverted five times in succession to mix the drugs. The syringes were mounted in an upright vertical position (plunger on top, port on bottom) with wire on a pegboard. Samples of the mixture were taken from the bottom port (via a 3-way stopcock) and from the top of the syringe (via a stopcock on an 18-gauge needle placed 5 mm through the plunger) at the following time intervals (min) from baseline: T0, T10, T30, T60, T120, T180, T240, T300. Remifentanil and propofol were quantified using specific and validated HPLC/ MS/ MS assays with automated online sample preparation. Results Concentrations of remifentanil were significantly greater at the top than the bottom of the syringes in groups A and B. Concentrations of propofol were significantly greater at the bottom than the top of the syringes in all groups. Conclusion Our data indicate that remifentanil solution and propofol emulsion are immiscible: remifentanil separates from propofol and rises to the top. Thus, concentrations of remifentanil and propofol delivered to patients from the same syringe during TIVA are not those expected and cannot be reliable. Remifentanil and propofol should be administered in separate syringes when used in combination for TIVA. [ABSTRACT FROM AUTHOR]

The article presents a case study of a female wildlife conservation worker who was presented with postartesunate delayed haemolysis (PADH) in severe Plasmodium falciparum malaria. Topics include the administration of the intravenous artesunate, the various tests she has undergone which includes blood test, abnormal liver function tests, and convalescent serological testing, and the aspects of the PADH risk due to artesunate drug.

Background: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). Methods: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60 ± 5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability ( r>0.6). Results: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. Conclusions: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA. [ABSTRACT FROM AUTHOR]