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Problems of stability were found for biomarkers of alcohol consumption: ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanols (PEths), and fatty acid ethyl esters (FAEEs) in whole blood. The purpose of this study was to establish a method for the determination of these four kinds of ethanol's non-oxidative metabolites in dried blood spots (DBS) by liquid chromatography tandem mass spectrometry (LC-MS/MS), and to evaluate their stability. In this method, 50 μL of human blood was spotted onto a filter paper for DBS analysis. Samples were extracted by methanol, reconstituted by 2-propanol, and injected into the LC-MS/MS system. Limits of detection were among 0.5-50 ng/mL, and deviations in accuracy and precision were all lower than 15% at three quality control levels. The stability of the four kinds of ethanol non-oxidative metabolites in DBS was investigated during a 90-day range under three temperatures, -20 °C, 4 °C, and 25 °C. EtG and EtS showed a high level of stability in DBS in the 90-day range, regardless of the temperature. FAEEs were unstable after three days. PEths showed stability within 15 days in postmortem DBS and 60 days in antemortem DBS, respectively, at all temperatures., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alcohol misuse affects a large part of the population worldwide, with high relapse rates reported even post-treatment. Treatments are also not always available, for example during the COVID-19 pandemic when social distancing measures affected the availability of in-person approaches. Novel treatments like Virtual Reality Therapy (VRT), delivered via a standard VR headset or a mobile device, may offer a flexible alternative for reducing drinking and assisting relapse prevention, but little is known about their acceptability. We therefore explored the acceptability of VRT alongside the treatment preferences of adult drinkers in an online survey. Participants were asked to consider and rank order a range of treatments typically offered by healthcare services alongside standard and mobile VRT in order to determine their relative preferences. Acceptability of each treatment was also established. Additional questions addressed potential predictors of VRT's acceptability including familiarity with each treatment option presented, prior experience of VR, hazardous drinking, perceived stigma, treatment uptake attitudes, gender, ethnicity, and mental health. Of 259 participants, more than half (52.9%) were drinking at hazardous levels. The majority of respondents (86.9%) expressed a preference for in-person treatments. Cognitive Behavioral Therapy, Counseling, and 12-Step Facilitation Therapy were considered the most acceptable treatments, whereas VRT, and particularly mobile VRT, were perceived as less acceptable than traditional treatments. Treatment familiarity and preferences, prior VR experience, mental health, treatment uptake attitudes, and perceived stigma were all associated with the acceptability of VRT. Psychoeducation and familiarization processes in delivery protocols, and in-person delivery of VRT, could increase the acceptability of VRT, particularly for people who are not regular technology users, or who require concurrent mental health support., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Yearly adult per capita consumption of alcohol in China between 2016 and 2019 decreased by 2.4 L of pure alcohol, or 33%. According to the World Health Organization, this decrease in consumption was accompanied by reductions in alcohol-attributable mortality of 23% between 2015 and 2019. This paper examines the contribution of alcohol control policies in China to these public health gains. A systematic search of the literature was conducted on alcohol control policies and their effectiveness in China as part of a larger search of all countries in WHO Western Pacific Region. In addition to articles on empirical evidence on the impact of such alcohol control policies, we also searched for reviews. The plausibility of changes of traditional alcohol control policies (taxation increases, availability restrictions, restriction on advertisement and marketing, drink-driving laws, screening and brief interventions) in explaining reductions of consumption levels and attributable mortality rates was explored. There was some progress in the successful implementation of strict drink-driving policies, which could explain reductions in traffic injuries, including fatalities. Other traditional alcohol control policies seem to have played a minimal role in reducing alcohol consumption and attributable harms during the time period 2016-2019. However, an anti-corruption campaign was extensive enough to have substantially contributed to these reductions. The campaign prohibited the consumption of alcoholic beverages in everyday life of government officials and thus contributed to a de-normalization of alcohol. While this anti-corruption campaign was the only policy to potentially explain marked decreases in levels of alcohol consumption and attributable mortality, more detailed research is required to determine exactly how the campaign achieved these decreases., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the possible impact of the COVID-19 pandemic on prevalence rates and self-reported changes in patterns of alcohol use among first-year university students in Spain, considering the risk of problematic alcohol use. A serial cross-sectional study based on the uniHcos project was carried out. Data from 10 518 first-year university students (73.3% female, mean age 19 (SD = 1.6)) collected between 2012 and 2022 were analysed. The evolution of the pooled prevalence rates during the time series was analysed and the risk of problematic alcohol consumption was assessed using the AUDIT. Also, self-reported changes in alcohol use patterns during the pandemic were assessed. According to the results, during the COVID-19 pandemic, the prevalence of alcohol use in the past 30-days was reduced (76.3% in 2019 vs. 63.7% in COVID-19) increasing again in the New Normal period. Thus, a similar pattern in the practice of binge drinking was observed. Regarding the AUDIT score, 21.7% (95%CI 20.9, 22.6) of the students had harmful alcohol consumption, with a higher proportion among males. In the multivariable logistic models, a higher AUDIT score was significantly associated (p-value < 0.001) with being male and living with roommates. According to self-reported changes in consumption patterns during the COVID-19 pandemic, a higher proportion of participants with harmful use reported an increase in alcohol consumption compared to those at low-risk (43% vs 19%). Finally, despite the overall reduction in drinking prevalence during COVID-19, changes were not equal for all students and depended on their previous level of problematic drinking, highlighting that this should be considered in the development of strategies against alcohol use in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Early developmental exposure to alcohol has been implicated in adverse effects on the brain, often associated with the onset of neurodevelopmental disorders. Moreover, maternal alcohol consumption during pregnancy has been linked to the manifestation of mental health disorders, such as depression and anxiety, in subsequent generations. These mood disturbances may be attributed to alterations in protein expressions related to depression and anxiety within the hippocampus. While the precise mechanisms remain elusive, it is likely that pre- and postnatal exposure to alcohol induces changes in hippocampus, potentially through epigenetic modifications. The FKBP5 gene, known to modulate the stress response, is particularly relevant in this context. We postulate that alcohol-induced methylation of the FKBP5 gene disrupts HPA axis function, thereby prompting individuals to anxiety-like and depressive-like behaviors. To investigate this hypothesis, female C57BL/6 pups were subjected to early alcohol exposure via intubation with ethanol mixed in artificial milk from Postnatal Day 3 to Day 20. The intubation control pups were subjected to the same procedures without ethanol or milk, and a non-intubated control group included. Anxiety-like and depressive-like behaviors were assessed using the open field test, plus maze test, forced swim test, and tail suspension test when the pups reached 3 months of age. For epigenetic analysis of the FKBP5 gene, genomic DNA was isolated from hippocampal tissues and subjected to bisulfite conversion to distinguish methylated and unmethylated cytosines. Then, methylation-specific PCR was performed to assess methylation levels. Pups exposed to early postnatal alcohol exhibited increased levels of depression-like behavior and susceptibility to anxiety-like behavior during adolescence, as verified by behavioral assessments. Methylation profiling revealed higher rates of methylation within the stress-associated gene FKBP5 in both the early postnatal alcohol-exposed cohort (13.82%) and the intubation control group (3.93%), in contrast to the control cohort devoid of stress or alcohol exposure. These findings suggest a potential epigenetic mechanism underlying the observed behavioral alterations, implicating FKBP5 methylation as a candidate mediator of the increased vulnerability to mood disorders following early postnatal alcohol exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The unclear mechanisms of ethanol metabolism in the brain highlight the need for a deeper understanding of its metabolic pathways. This study used in vivo microdialysis to simultaneously sample ethanol and its metabolites, acetaldehyde and acetate, in the rat striatum following self-administration of ethanol, emphasizing the natural oral exposure route. To enhance the self-administration, rats underwent two-bottle-choice and limited access training. Dialysate samples, collected every 10 minutes for 2.5 hours, were analyzed using gas chromatography with flame ionization detection (GC-FID). The measured time courses of dialysate concentrations of ethanol, acetaldehyde, and acetate provided insights into dynamics of ethanol metabolism. Notably, in a subject with low ethanol consumption (0.29 g/kg), the concentration of acetaldehyde remained below the limit of detection throughout the experiment. However, the acetate concentration was clearly increased after ethanol consumption in this subject and was comparable to that of other rats with higher ethanol consumption. Compared with focusing only on peak values in the time-courses of concentrations of ethanol and its metabolites, calculating areas under curves provided better models of the relationships between ethanol intake and individual ethanol metabolites, as indicated by the r-square values for the linear regressions. This approach of using the area under the curve accounts for both the amplitude and duration of the concentration profiles, reducing the impact of variations in individual drinking patterns. In vivo microdialysis enables concurrent sampling of brain metabolites during oral ethanol administration, contributing insights into metabolite dynamics. To our knowledge, this paper is the first to report measurement of all three analytes in the brain following self-administration of ethanol. Future studies will explore regional variations and dynamics post-ethanol dependence, further advancing our understanding of ethanol metabolism in the brain., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Orexin in both the lateral hypothalamus (LH) and medial septum (MS) is involved in sleep- and consciousness-related conditions. Since orexin modulates the intoxicating as well as rewarding effects of ethanol, this study focused on the role of orexin-projecting neurons from the LH to the MS, and this neurocircuit's role in mediating the sedative effects of alcohol. Drinking-in-the-Dark (DID) behavior was also assessed as a measure of the role of the LH-MS pathway in modulating binge-like ethanol intake, with a particular focus on sex differences in both behavioral paradigms. Male and female Hcrt-ires-cre mice received cannulation in the MS, while the LH was injected bilaterally with cre-dependent excitatory (Gq) Designer Receptor Exclusively Activated by Designer Drug (DREADD), inhibitory (Gi) DREADD or control virus. All subjects received a 3.75 g/kg dose of 20 % ethanol intraperitoneally and the sedative effect was assessed by the loss of righting reflex (LORR). After behavioral testing, brains were used for c-Fos immunohistochemistry analyses. A separate cohort of mice was used for a 2-week DID protocol using excitatory (Gq) DREADD and control virus. Gq DREADD-induced activation of the orexin neurocircuitry from the LH to the MS significantly reduced sedation time in both female and male mice. Furthermore, CNO treatment failed to alter ethanol sedation times in both animals expressing Gi DREADDs and control virus. There were no significant differences in blood ethanol concentrations (BECs) in any experimental group, suggesting that changes in sedation were not due to treatment-induced alterations of ethanol metabolism. Interestingly, in the DID study, only male mice decreased their ethanol consumption when Gq DREADDs were activated. These results provide novel evidence on the role played by this orexinergic LH to MS circuit on the sedative effects of ethanol and ethanol consumption in a sex-dependent manner. Thus, the MS should be considered further as a novel sexually dimorphic target., Competing Interests: Declaration of competing interest The authors declare no competing financial interests. Dr. Thiele owns shares in Glauser Life Sciences, a company that aims to develop therapeutics for mental health disorders. The work that is presented in this paper is not directly related to the scientific aims of Glauser Life Sciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Autonomic symptoms in alcohol withdrawal syndrome (AWS) are associated with a sympathetic-driven imbalance of the autonomic nervous system. To restore autonomic balance in AWS, novel neuromodulatory approaches could be beneficial. We conducted a pilot trial with percutaneous auricular vagus nerve stimulation (pVNS) in AWS and hypothesized that pVNS will enhance the parasympathetic tone represented by a reduction of pupillary dilation in a parasympatholytic pharmacological challenge., Methods: Thirty patients suffering from alcohol use disorder, undergoing AWS, and stable on medication, were recruited in this open-label, single-arm pilot trial with repeated-measure design. Peripheral VNS (monophasic volt impulses of 1 msec, alternating polarity, frequency 1 Hz, amplitude 4 mV) was administered at the left cymba conchae for 72 h, followed by pupillometry under a tropicamide challenge. We assessed craving with a visual analog scale. We used pupillary mean as the dependent variable in a repeated-measures ANOVA (rmANOVA)., Results: A repeated-measures ANOVA resulted in a significant difference for pupillary diameter across time and condition (F (2,116)  = 27.97, p < .001, η p 2  > .14). Tukey-adjusted post hoc analysis revealed a significant reduction of pupillary diameter after pVNS. Alcohol craving was significantly reduced after pVNS (p < .05, Cohen's d = 1.27)., Conclusion: Our study suggests that pVNS activates the parasympathetic nervous system in patients with acute AWS, and that this activation is measurable by pupillometry. To this end, pVNS could be beneficial as a supportive therapy for AWS. Potential confounding effects of anti-craving treatment should be kept in mind., Competing Interests: Declaration of competing interest SK holds, shares, and is employed by AURIMOD GmbH. JCS holds shares of the Multisana GmbH. All other authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: New-generation transdermal monitors such as the ION Research Alpha Prototypes (ION RAP) hold promise for real-time alcohol measurement, with improvements in design features such as sampling frequency, size, and comfort. This paper aims to provide the first comparisons of the wrist-worn enzyme-based ION RAP and the fuel cell-based SCRAM-CAM against breath alcohol concentration (BrAC) readings., Methods: Participants (N = 23) completed a total of 69 laboratory alcohol administration sessions while wearing both a prototype of the ION RAP wristband and a SCRAM-CAM ankle monitor; they also gave breath samples each 10 min. Analyses focused on latencies of transdermal alcohol concentration (TAC) after alcohol ingestion, correlations, and cross-correlations between BrAC and TAC measurements., Results: A high failure rate of the ION RAP was observed (61.5% of the sessions were excluded due to the sessions not containing enough valid data). On average, the SCRAM-CAM and ION RAP detected alcohol 43 (SD = 21) and 50 (SD = 27) minutes after the first drink, with peak values reached after 138 (SD = 47) and 154 (SD = 56) minutes, respectively. SCRAM-CAM TAC peak (r = 0.185, p = 0.375) and area under the curve (AUC; r = 0.320, p = 0.118) showed small- and medium-sized correlations to BrAC. ION RAP TAC peak (r = -0.082, p = 0.698) and AUC (r = 0.040, p = 0.852) correlations to BrAC were close to zero., Conclusions: In this study, the new-generation ION RAP and the traditionally used SCRAM-CAM show similar delays in detection and similar TAC curves over time, despite using either enzyme- or fuel cell-based technologies, respectively. Due to high failure rates of the ION RAP prototypes and close to zero correlations to BrAC, further developments and improvements of these TAC wristbands are required for reliable and valid use in real-time alcohol measurement., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Acute alcohol intoxication impairs cognitive and psychomotor abilities leading to various public health hazards such as road traffic accidents and alcohol-related violence. Intoxicated individuals are usually identified by measuring their blood alcohol concentration (BAC) using breathalyzers that are expensive and labor intensive. In this paper, we developed the Audio-based Deep Learning Algorithm to Identify Alcohol Inebriation (ADLAIA) that can instantly predict an individual's intoxication status based on a 12-s recording of their speech., Methods: ADLAIA was trained on a publicly available German Alcohol Language Corpus that comprises a total of 12,360 audio clips of inebriated and sober speakers (total of 162, aged 21-64, 47.7% female). ADLAIA's performance was determined by computing the unweighted average recall (UAR) and accuracy of inebriation prediction., Results: ADLAIA was able to identify inebriated speakers - with a BAC of 0.05% or higher - with an UAR of 68.09% and accuracy of 67.67%. ADLAIA had a higher performance (UAR of 75.7%) in identifying intoxicated speakers (BAC > 0.12%)., Conclusion: Being able to identify intoxicated individuals solely based on their speech, ADLAIA could be integrated into mobile applications and used in environments (such as bars, sports stadiums) to get instantaneous results about inebriation status of individuals., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alcohol addiction is a chronic relapsing disease that is progressive and has severe detrimental health outcomes. The use of natural products has become popular for the treatment of side effects of drugs and substance abuse. Linalool is a monoterpenoid that exhibits several effects on the central nervous system. Linalool was identified to have beneficial effects on different mechanisms that are relevant in drug addiction or substance use disorder. The primary aim of the present study was to evaluate the therapeutic effect of linalool on the rewarding properties of alcohol in mice. Conditioned place preference (CPP) was established by intraperitoneal (i.p.) injection of ethanol (2 g/kg) during an 8-day conditioning trial. The effects of acamprosate and linalool on the rewarding properties of ethanol were tested in mice who received linalool (12.5, 25, and 50 mg/kg, i.p.) and acamprosate (300 mg/kg, i.p.) 30 min before each ethanol injection. CPP was extinguished by repeated testing, throughout which conditioned mice were administered daily linalool. Mice were lastly examined for reinstatement provoked by i.p. administration of single low-dose ethanol (0.4 g/kg, i.p.). Treatment with linalool reduced the acquisition and reinstatement, and precipitated the extinction of ethanol-induced CPP in mice. Acquisition and reinstatement of alcohol-induced CPP were significantly reduced by acamprosate, which also precipitated extinction. Ethanol alone and the combination with linalool or acamprosate did not alter locomotor activity. The results of this study suggest that linalool may have pharmacological effects for the treatment of alcohol addiction. In addition, further investigation is required to fully explore the benefits and possible adverse effects of linalool on alcohol addiction., Competing Interests: Declaration of competing interest The author(s) declare that they have no known competing commercial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The aim of this paper is to examine the alcohol-related consequences experienced by adults who reported a 2-week period of low mood and identified as a 'self-medicator' compared to those who do not. Our focus is on assessing whether the conceptualization of alcohol use disorder severity differs across adult drinkers who self-medicate with alcohol during a period of low mood, compared to those who do not. This study used secondary data from the NESARC survey. The analytic sample consisted of 5945 participants who answered questions from the alcohol abuse/dependence (alcohol experiences) section, in the last 12 months. The sample was split into four groups by whether they self-medicated with alcohol or not, drank alcohol in the last year, and their drinking class. The findings indicated that a one-factor model was the best fit, and all items were a strong indicator of alcohol use disorder. The two-parameter model had the best fit, indicating that the diagnostic criteria were placed as a good fit along a continuum of severity. It was revealed that the hazardous drinking group who self-medicated, experienced more consequences even at low levels of severity. As the self-medicating hazardous drinking group also showed the highest estimates for alcohol use disorder severity, this may indicate that this group is composed of high-functioning self-medicators who are trying to regulate their drinking, and may not be as clinically high risk as expected, due to their drinking patterns., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Wrist-worn alcohol biosensor technology has developed rapidly in recent years. These devices are light, easy to wear, relatively inexpensive, and resemble commercial fitness trackers. As a result, they may be more suitable for a wide range of clinical and research applications. In this paper, we describe three pilot projects examining the associations between reported drinking behavior and transdermal alcohol concentration (TAC) derived from a new, wrist-worn alcohol biosensor (BACtrack Skyn) in diverse participant groups and settings. Study 1 (N = 3) compared Skyn-derived TAC with that from an ankle-worn alcohol sensor (SCRAM CAM) and breath alcohol concentration (BrAC) in a laboratory setting. Study 2 (N = 10) compared Skyn TAC with BrAC during a naturalistic drinking episode in the field. Study 3 (N = 12) used the Skyn to monitor alcohol use in the field for 2 weeks. Studies 2 and 3 also collected usability and acceptability data from participants. The results of Study 1 showed that the Skyn produced a TAC curve that closely resembled that of the validated SCRAM CAM anklet. In Study 2, Skyn detected drinking for all 10 participants (peak BrAC range: 0.02-0.21) with an average delay of 35.6 ± 10.2 min after the start of self-reported drinking. In Study 3, Skyn reliably recorded continuous TAC data showing multiple drinking episodes over the monitoring period. Participants in Studies 2 and 3 both reported Skyn as highly acceptable. Collectively, the results of these pilot studies show that the Skyn was able to reliably detect drinking events in the laboratory and natural environments. We offer suggestions for further refinements of alcohol biosensors and accompanying analytic software that may facilitate adoption of these devices as cost-effective, user-friendly, and reliable tools to passively and accurately assess alcohol use in the field., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Alcohol use disorder (AUD) is highly comorbid with other substance use disorders (SUDs) as well as other psychiatric disorders, such as anxiety, depression, and Borderline Personality Disorder (BPD). However, studies of persons with AUD rarely account for its comorbidity with other SUDs. Some research suggests that BPD symptoms reflect an important connection between internalizing disorders and SUDs. The current study investigated: 1) the levels of trait anxiety and symptoms of depression and BPD in persons with an AUD as a function of comorbid SUDs (cannabis use disorder - CUD) and other substance use disorder (oSUD), and 2) the influence of BPD on the association between severity of overall lifetime SUD symptoms (AUD + CUD + oSUD) and both trait anxiety and symptoms of depression., Method: Trait anxiety and symptoms of depression and BPD were assessed in 671 young adults (351 men; 320 women; mean age 21 years) separated into four groups: Controls (n = 185), AUD-only (134), AUD + CUD (n = 210), and AUD + oSUD (n = 142)., Results: Trait anxiety and symptoms of depression and BPD were elevated in all AUD groups compared with controls, and in the AUD + oSUD group compared with all other groups as well. Structural models also indicated that BPD symptoms accounted for all of the variance in lifetime SUD symptoms associated with Trait Anxiety, and a significant portion of the variance in lifetime SUD symptoms associated with depression symptoms., Conclusion: Results indicate that when AUD is comorbid with oSUD, it is associated with more severe AUD symptoms and higher levels of trait anxiety and symptoms of both depression and BPD. The results also indicate that BPD symptoms account for the majority of the variance in SUD symptoms associated with both trait anxiety and depression, suggesting that a considerable amount of the internalizing symptomatology in AUD/SUDs is associated with BPD psychopathology., Competing Interests: Declaration of competing interest The authors of this paper declare that they have no conflict of interest relating to the study reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fetal ethanol exposure represents a risk factor for sudden infant death syndrome, and the respiratory effects of fetal ethanol exposure promote hypoxic ischemic consequences. This study analyzes central ethanol's effects upon breathing plasticity during an ontogenetic stage equivalent to the human third gestational trimester. Ethanol's unconditioned breathing effects and their intervention in learning processes were examined. Since central ethanol is primarily metabolized via the catalase system, we also examined the effects of early history with the drug upon this system. During postnatal days 3, 5, and 7 (PDs 3-7), pups were intracisternally administered with vehicle or ethanol (300 mg%). They were tested in a plethysmograph scented or not scented with ethanol odor. The state of intoxication attenuated the onset of apneas, a phenomenon that is suggestive of ethanol's anxiolytic effects given the state of arousal caused by the novel environment and the stress of ethanol administration. At PD9, pups were evaluated when sober under sequential air conditions (initial-normoxia, hypoxia, and recovery-normoxia), with or without the presence of ethanol odor. Initial apneic episodes increased when ethanol intoxication was previously associated with the odor. Pups then ingested ethanol, and brain catalase activity was determined. Pre-exposure to ethanol intoxication paired with the odor of the drug resulted in heightened enzymatic activity. Central ethanol exposure appears to exert antianxiety effects that attenuate apneic disruptions. However, during withdrawal, the cues associated with such effects elicit an opposite reaction. The activity of the catalase system was also dependent upon learning processes that involved the association of environmental stimuli and ethanol intoxication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Alcohol-induced blackouts are a common high-risk outcome of heavy episodic drinking and are considered a marker of problematic alcohol consumption. One's estimates of the prevalence and peer approval of heavy episodic drinking (i.e., social norm perception, descriptive and injunctive norms, respectively) strongly relate to high-risk alcohol consumption. However, it is unknown whether the intention to blackout and the occurrence of alcohol-induced blackouts also associates with these estimates. Therefore, the purpose of this paper is to explore the relation between participants' social norm perception and alcohol-induced blackout intentions and recent blackout history., Method: A total of 4430 participants completed an online survey with an average age of 19.97 (SD = 1.70) years. A series of ANOVAs and a structural equation model examined the relation between social norm perception, intention to blackout, and recent blackout history., Results: In the structural equation model, the social norm variables (descriptive and injunctive norms) were associated with higher levels of blackout intentions and recent blackout history. The global fit indices suggest that the data fit the model, χ 2 (n = 4248, 442) = 7755.90, p < .001, CFI = .96, TLI = .96, RMSEA = .06 (CI90 .061-.064)., Conclusions: Participants with a higher likelihood of having a past 30-day history of alcohol-induced blackouts and higher blackout intentions believed that many of their peer groups approved of certain alcohol-related behaviors and that their peer groups drink frequently and drink higher quantities. Future interventions may assess the impact of adjusting social norms on both the intention to blackout and experiencing blackouts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Wearable alcohol biosensors have emerged as a valuable tool for noninvasive, objective, and continuous monitoring of alcohol consumption. However, to date their research and clinical applications have been limited by several factors including large size, high cost, and social stigma. In contrast, recently developed wrist-worn alcohol biosensors are smaller, less expensive, and may be more acceptable for daily use. However, these devices are at the prototype phase and have just begun to be tested for research applications. In this paper, we describe our experiences with two prototypes of these new wrist-worn alcohol biosensors (i.e., Quantac Tally and BACtrack Skyn) and their associated smartphone applications in both a controlled laboratory setting and the real-world environment. Our preliminary experiences with these devices highlight their advantages including comfort, high participant acceptability, and good compliance. However, there are various limitations that should be addressed prior to future research applications of these biosensors, including large interpersonal variations in transdermal alcohol readings, lack of immediately applicable data analysis/interpretation software, and poor battery life after a few months. More research is also needed to further validate the new biosensors, and investigate individual (e.g., skin thickness, gender differences) and environmental factors (e.g., humidity, temperature) contributing to the variations in transdermal alcohol readings measured by wrist-worn alcohol biosensors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Despite extensive evidence of heterogeneity in intimate partner violence (IPV) perpetrator profiles, there has been little research into neuropsychological deficits that might help us understand differences within this violent population. Moreover, studies on this topic have not paid much attention to the role of alcohol abuse in neuropsychological domains of IPV perpetrators. Hence, the current study was designed to examine neuropsychological differences among individuals who have committed domestic violence with high (n = 28, HA) and low (n = 35, LA) levels of alcohol consumption, and non-violent individuals (n = 37) to establish differential neuropsychological profiles. An exhaustive neuropsychological assessment battery was employed which combined the computer-based Cambridge Neuropsychological Test Automated Battery with pencil-and-paper measures. Compared to controls, HA IPV perpetrators had slower processing speed and significantly more impairments in attentional set-shifting or switch attention, working and long-term memory, cognitive flexibility, planning, decision-making, emotion decoding skills, and perspective taking. Furthermore, there were differences between IPV perpetrator subgroups in attentional set-shifting or switch attention and cognitive empathy, with HA IPV perpetrators displaying more severe impairments in both cognitive domains than LA IPV perpetrators. Finally, the LA IPV perpetrators had significantly more impairments in working and long-term memory, executive functioning, and emotion decoding skills than controls, but they did not differ in processing speed, attentional set-shifting or switch attention, decision making, or perspective taking. Thus, the current findings suggest that IPV perpetrators with neuropsychological difficulties, especially those who are heavy drinkers, may have the greatest need for cognitive interventions. These cognitive deficits could be employed as targets for developing specific cognitive rehabilitation programs adjuvant to psychotherapeutic intervention for IPV perpetrators., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Dr. Kathleen Sulik (Kathy) has spent 35 years studying fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). Beginning with her landmark 1981 Science paper describing the early gestational window when alcohol can cause the craniofacial malformations characteristic of FAS, Kathy has contributed a vast amount of research furthering our knowledge of FASD. After her seminal work that definitively demonstrated that alcohol is the causative factor in FAS, she and her lab went on to explore and define the stage-dependent effects of early gestational alcohol exposure on the face and brain in numerous different ways throughout her career. She explored and discovered numerous mechanisms of alcohol's effects on the embryo, as well as describing several genetic factors that can modify susceptibility to developmental alcohol exposure. She did not restrict her research to the face and brain; her lab described in intricate detail the effects of developmental alcohol exposure on many different organs, including the heart, ears, kidneys, and limbs. In addition to her research, and in conjunction with NIAAA and the National Organization on Fetal Alcohol Syndrome (NOFAS), Kathy developed several FASD prevention curricula that are still in use today. Finally, as part of her drive to eradicate FAS and FASD, Kathy labored tirelessly with public policy makers to change how FASD is viewed by the public, how FASD is identified in affected individuals, and how FASD is studied by researchers. While no article could fully cover Kathy's contributions to FASD research and prevention, or her other contributions to embryology and teratology, this review will attempt to illustrate some of the highlights of Kathy's remarkable career., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown. Recent studies in animal models have suggested that epigenetic factors are also responsible for the transmission of alcohol-related pathologies across generations. Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimutations are inherited in the offspring. This paper reviews evidence for multigenerational and transgenerational epigenetic inheritance of alcohol-related pathology through the germline. We also review the literature on the epigenetic effects of alcohol exposure on somatic cells in brain, and its contribution to AUDs and FASDs. We note gaps in knowledge in this field, such as the lack of clinical studies in human populations and the lack of data on epigenetic inheritance via the female germline, and we suggest future research directions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This paper presents a study of the effect of alcohol consumption on individual health status and health care utilization in Ireland using the 2007 Slán National Health and Lifestyle Survey, while accounting for the endogenous relationship between alcohol and health. Drinkers are categorized as those who never drank, non-drinkers, moderate drinkers, or heavy drinkers, based on national recommended weekly drinking levels in Ireland. The drinking-status equation is estimated using an ordered probit model. Predicted values for the inverse mills ratio are generated, which are then included in the health and health-care utilization equations. Differences in health status for each category of drinker are examined, and the relationship between both alcohol consumption and health with a host of other personal and socio-economic variables is also identified. Given that the measure of health status available is self-assessed, the effect of alcohol consumption on health-care utilization is also analyzed as an alternative measure of health. Findings show that in Ireland, moderate drinkers enjoy the best health status. More moderate drinkers report having very good or excellent health compared with heavy drinkers, non-drinkers, or those who never drank. While heavy drinkers do not report having as good a health status as moderate drinkers, they are better off in terms of health when compared with non-drinkers and those who are lifetime abstainers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This paper presents a study of the effects of alcohol consumption on household income in Ireland using the Slán National Health and Lifestyle Survey 2007 dataset, accounting for endogeneity and selection bias. Drinkers are categorised into one of four categories based on the recommended weekly drinking levels by the Irish Health Promotion Unit; those who never drank, non-drinkers, moderate and heavy drinkers. A multinomial logit OLS Two Step Estimate is used to explain individual's choice of drinking status and to correct for selection bias which would result in the selection into a particular category of drinking being endogenous. Endogeneity which may arise through the simultaneity of drinking status and income either due to the reverse causation between the two variables, income affecting alcohol consumption or alcohol consumption affecting income, or due to unobserved heterogeneity, is addressed. This paper finds that the household income of drinkers is higher than that of non-drinkers and of those who never drank. There is very little difference between the household income of moderate and heavy drinkers, with heavy drinkers earning slightly more. Weekly household income for those who never drank is €454.20, non-drinkers is €506.26, compared with €683.36 per week for moderate drinkers and €694.18 for heavy drinkers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While rats have been predominantly used to study operant ethanol self-administration behavior in the context of dependence, several studies have employed operant conditioning procedures to examine changes in ethanol self-administration behavior as a function of chronic ethanol exposure and withdrawal experience in mice. This review highlights some of the advantages of using operant conditioning procedures for examining the motivational effects of ethanol in animals with a history of dependence. As reported in rats, studies using various operant conditioning procedures in mice have demonstrated significant escalation of ethanol self-administration behavior in mice rendered dependent via forced chronic ethanol exposure in comparison to nondependent mice. This paper also presents a summary of these findings, as well as suggestions for future studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol's acute and long-term pharmacological consequences., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The severity of alcohol dependence can be estimated by the number of DSM-IV criteria that are fulfilled for this disorder. This paper describes the proportions in a general population sample that meet different numbers of diagnostic criteria for alcohol dependence and their association with drinking and social background factors. Data came from a random, cross-sectional, self-report survey of adults from 12 Swedish communities. 28,800 persons, age 19-70, were surveyed through postal questionnaires. 14,706 questionnaires (51%) could be used for analysis. Alcohol dependence was assessed by questions relating to the seven DSM-IV criteria for alcohol dependence. Alcohol consumption and social background factors were examined in relation to alcohol dependence. A total of 73.8% of the general population fulfilled no criteria for alcohol dependence; 4.0% reported 3 or more criteria and qualified for the diagnosis of alcohol dependence. There were trends toward an increasing number of dependence criteria with increasing consumption levels and negative social background factors. The majority of people with alcohol dependence however did not drink at the highest consumption levels, did not live alone, and were not unemployed. Given the current definition of alcohol dependence the majority of people have few criteria fulfilled (3 or 4) and few social problems. This has important implications for treatment as dependence with low severity may require less treatment and less specialist involvement., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Metabolic perturbations associated with HIV and antiretroviral therapies are widespread. Unfortunately, research has predominantly focused in cardiometabolic problems, neglecting other important areas. In fact, the immune-calcium-skeletal interface has been understudied despite its potential relevance in people living with HIV (PLWH). Using a case-control methodology, 200 PLWH receiving medical care were enrolled and stratified according to hazardous vs. non-hazardous alcohol intake (HAU vs. non-HAU) and calcium (Ca) levels by analyzing baseline data. The group was chosen to represent relatively "pure" HAU with minimal drug use and no psychiatric diagnoses. With these narrow parameters in place, we found evidence that HAU significantly increases TNF-α levels compared to Non-HAU (2.8 ± 0.6 vs. 1.9 ± 0.3 pg/ml, p = 0.05) and decreases blood Ca levels (9 ± 0.6 vs. 9.4 ± 0.5, p = 0.03). Our analyses also suggest that chronic inflammation, as indicated by increased TNF-α levels, is associated with hypocalcemia (hypoCa <8.6). Despite the limited prevalence of hypoCa, these findings are clinically significant given that hypoCA PLWH exhibited decreased CD4 (253 ± 224 vs. 417.7 ± 281, p = 0.02), B cells (147 ± 58 vs. 248 ± 151, p = 0.03) and NK cells (146.8 ± 90 vs. 229 ± 148, p = 0.008) and elevated CD8 (902.5 ± 438 vs. 699 ± 510, p = 0.09) compared to those with normal calcium. Furthermore, calcium effects on viral load were also evident with hypoCA exhibiting the highest loads (140,187 ± 111 vs. 35,622 ± 7770 HIV copies, p = 0.01). Multivariate analyses confirmed the significance of hypoCa in predicting viroimmune parameters. This paper provides the first evidence that hypoCa accounts for some of the variation in viroimmune measures in HAART recipients and suggests that hypoCa may be mediating alcohol's deleterious effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The aim of this paper is to study polymorphism in the TH, ADH1B, ADH1C, ALDH2 and CYP2E1 genes so as to ascertain whether it is associated with excessive consumption of alcohol. The SNPs rs6356 of TH, rs1229984, rs2066702 of ADH1B; rs698, rs1693482 of ADH1C; rs671 of ALDH2; rs72559710, rs55897648, rs6413419, rs3813867, rs2031920, rs6413432 of CYP2E1 were studied in a sample of 172 high-level patients and 150 fully non-drinkers controls. Genotyping was performed using Rt-PCR with Taqman probes. SNPs located at ALDH2 and CYP2E1 showed no heterozygosity. Frequency distribution showed significant differences between the two groups studied for loci TH and ADH1B. The genotype Val/Val of TH locus increased in risk 1.988 times (95% CI: 1.006-3.930) that the subjects carrying the genotype Met/Met; and the genotype ADH1B*1/*1 of ADH1B locus increased in risk 3.811 times (CI: 1.660-8.749) that the subjects carrying the genotype ADH1B*1/*2. Alleles Val and ADH1B*1 may therefore increase the risk of the onset and development of this illness., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The present paper summarizes experimental data demonstrating the reducing effect of direct agonists and positive allosteric modulators (PAMs) of the gamma-aminobutyric acid(B) (GABA(B)) receptor on different alcohol-related behaviors. Different lines of evidence indicate that direct agonists, including baclofen, effectively suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking, and alcohol's reinforcing, rewarding, stimulating, and motivational properties in rats and mice. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, opened a new avenue of research in GABA(B) pharmacology. Accumulating lines of evidence suggest that PAMs retain baclofen's capcity to suppress alcohol consumption and alcohol's reinforcing and motivational properties in rats; these effects occur at doses far from those producing behavioral toxicity.

Previous studies have identified quantitative trait loci (QTL) in the inbred high and low alcohol-sensitive rat (IHAS1 and ILAS1) strains. The original development of the strains involved selection for ethanol sensitivity based on duration of the loss of the righting reflex (LORR) after a standard dose of ethanol. This paper confirms some of these QTL using a short-term selection procedure based on the difference between the blood ethanol level at LORR and regain of the righting response. An F(2) population of rats was developed by a reciprocal cross of IHAS1 and ILAS1 rats. Selection for five generations was carried out using delta-blood ethanol concentration (dBEC) as the selection trait, where dBEC=BECLR (BEC at loss of righting reflex)-BECRR (BEC at regain of righting reflex). The lines were labeled tolerant (TOL) or sensitive (SENS). Approximately one-third of the offspring for each generation in each line were genotyped using DNA markers that had been previously found to be linked to QTL on chromosomes 1, 2, 5, 12, and 13. By the fifth generation of selection, the lines showed a very large difference in dBEC, BECRR, and duration of LORR; BECLR showed little segregation during the selection, and latency to lose the righting reflex showed none. IHAS allele frequency increased in the SENS line for markers on chromosomes 1, 5, 12, and 13 while ILAS allele frequency increased in the TOL line. These results were in good agreement with the two previous QTL studies. On chromosome 2, the selection resulted in an accumulation of ILAS alleles in both lines. This study provides independent confirmation of the location of QTL on chromosomes 1, 5, 12, and 13 for ethanol sensitivity. It also suggests that genetic differences in duration of LORR are mediated primarily by the dBEC phenotype.

In this paper, we reviewed all existing studies using electroencephalography (EEG) in infants and children with known prenatal exposure to alcohol (PEA). The guiding purposes of the review were to determine if (1) EEG is a useful neuroimaging technique for investigating the brain correlates of PEA in infants and children, (2) there are indeed consistent EEG correlates of PEA in literature, and (3) these EEG correlates can be framed within a coherent picture of emerging implications for the study of PEA and its effects. The review confirms that EEG techniques have proven useful in indicating evidence of differential effects of patterns of PEA and timing in early fetal development and impairment of brain maturation in older children. In general, these techniques could be important in functional assessment of the brain of children affected by PEA, especially if used in conjunction with other neuroimaging techniques. The reviewed studies also suggest that although the impact on sensory and cognitive functions may involve extensive neural networks, there are EEG correlates of PEA which may in the future lead to the identification of neurophysiologic markers. A consistent aspect that emerges from the EEG data is that converging evidence from the study of different systems and processes suggests that PEA may almost invariably have consequences for later neurocognitive development.

The rewarding properties of used and abused substances are related to their ability to modulate central processes subserving mood, cognition, and behavior. Research into the motivationally relevant factors mediating substance use and abuse among human beings, including tobacco smoking, can strategically benefit from the utilization of noninvasive brain function measures that are able to probe the neurobiology of brain states in concert with substance ingestion. This paper reviews investigations from my laboratory with the use of neuroelectric tools, by means of quantitative electroencephalography, for the purpose of characterizing the central response to cigarette smoking. Prominent in these strategies is the acute smoking paradigm, whereby measures are focused on the profiling of central responsivity to smoke inhalation from a single cigarette and administration of test doses of nicotine. Complementing this approach are studies (1) in which receptor antagonists are administered in an attempt to explore putative transmitter systems regulating the acute smoking-induced electroencephalographic response and (2) in which electroencephalographic profiles of acute smoking are compared with electroencephalographic profiles resulting from administration of single doses of psychotropic substances. Completing these studies are attempts to monitor the electrocortical correlates of repeated smoking exposure and smoking deprivation, which, together with investigations examining smoker vs. nonsmoker differences and the effects of chronic life-long smoking, provide objective insights into the neuroelectrophysiology underlying the smoking habit.

The aim of this paper is to 'look behind the statistics' and to study alcohol-related problems over time and to portray the recovery (treated and untreated) from these problems over the life course in a subset of 41 males, defined as DSM-IV alcoholics from the Lundby general population project. The subjects were interviewed with semi-structured interviews by a psychiatrist. There was only minimal attrition. An analysis was made of the distribution of alcohol-related problems among the current alcoholic group compared to the recovered one at follow-up. Due to the limited number of subjects the calculations were mainly descriptive. The dominant problems were medical (64% vs. 25%), mental (45% vs. 17%), family (27% vs. 0%) and work (18% vs. 8%). The overall functioning assessed by the GAF scale implied a change from continuous to transient symptoms and problems in the recovered group. The subjects' attributions of reasons for recovery were social stabilization (84%), treatment (58%), family and peer pressure (58%) and medical complications (33%). It is argued that the qualitative findings might be used to complement the large statistical investigations in order to understand how to link alcohol-related problems and social consequences to the life course studies.

The present paper reviews the drug discrimination studies, both from the literature and from this laboratory, conducted to investigate the pharmacological profile of the discriminative stimulus effects of gamma-hydroxybutyric acid. Collectively, the results of these studies suggest that: (1) the discriminative stimulus effects of gamma-hydroxybutyric acid are composed of different cues, each one being the effect of gamma-hydroxybutyric acid on a specific receptor system; (2) the proportion of each component cue varies as the training dose of gamma-hydroxybutyric acid is increased; (3) the gamma-aminobutyric acid B-mediated cue is a major ingredient of the mixed stimulus of gamma-hydroxybutyric acid, but it is more prominent at high training doses than at low training doses of gamma-hydroxybutyric acid; and (4) positive modulation of the gamma-aminobutyric acid A receptor is a relevant part of the discriminative stimulus effects of low gamma-hydroxybutyric acid doses. Finally, data indicating symmetrical generalization between the discriminative stimulus effects of a specific range of doses of gamma-hydroxybutyric acid and those of ethanol are discussed in regard to their further support of the hypothesis that gamma-hydroxybutyric acid may exert its antialcohol effects through a substitution mechanism.

Dipole source localization promises to enhance knowledge about the structural and functional processes underlying differences in scalp-recorded ERPs observed between normal and patient populations. In this paper the Cuffin and Cohen (1) four-compartment model of volume conduction is used to examine the effects of variations in size of different compartments on scalp-recorded potentials. Using single discrete current dipoles located various distances from the center of the head, the effect of varying the thickness of the superficial extra-sulcal subarachnoid layer of CSF and the thickness of the skull are examined. Changing the thickness of the CSF layer alters amplitude recorded at the scalp and also alters the topographic distribution of the potential; these effects are more pronounced the closer the dipole source is to the surface. Changes in skull thickness have similar, but even greater effects.

The involvement of aldehyde adducts in the etiology of alcoholism continues to be supported by a number of experimental findings. These metabolites are synthesized endogenously from a condensation reaction of a biogenic aldehyde with a catechol- or indole-amine and act in the brain to augment or suppress the drinking of ethyl alcohol. When given by the intracerebroventricular route in an animal which does not prefer alcohol, certain tetrahydro-isoquinolines and beta-carbolines can augment significantly the voluntary intake of alcohol even in aversive concentrations. This paper describes the historical background and current status of the "Multiple Metabolite" theory of alcoholism. The recent identification of anatomical structures in the limbic-midbrain, limbic-forebrain of the Sprague-Dawley rat, which mediate changes in the intake of alcohol induced by tetrahydropapaveroline (THP) is also described. When injected in a low dose of 25 ng in a specific site, over a 3-day period, THP induces persistent increases in the intake of alcohol even in aversive concentrations. These THP-reactive sites comprise the substantia nigra, reticular formation, medial lemniscus, zona incerta, medial forebrain bundle, nucleus accumbens, olfactory tubercle, lateral septal nucleus, preoptic area, stria terminalis, and rostral hippocampus. A higher dose of 250 ng THP microinjected at homologous loci tends to inhibit the rat's self-selection of alcohol or exert no effect on drinking. Morphological mapping of histologically identified sites sensitive to THP revealed a distinct "circuitry" of neuronal structures overlapping both dopaminergic and enkephalinergic pathways. This "circuit" extends from the tegmental-nigral area of the midbrain rostrally to structures within the limbic-forebrain. When a THP-reactive structure, the N. accumbens, was lesioned by either of two neurotoxins, 6-hydroxydopamine or 5.7-dihydroxytryptamine, the rats' preference for alcohol increased sharply. This suggests that impairment of transmitter release, denervation supersensitivity or other perturbation of receptor function within this and other structures play a part in the aberrant drinking of alcohol. It is envisaged that a dopamine-enkephalin link underlies the mechanism for the onset, maintenance and permanency of alcohol preference generated by an aldehyde adduct. Finally, the "Two-Channel, Brain Metabolite" theory of alcoholism proposes that the transitory presence of an endogenously formed aldehyde adduct within cells of the brain causes a permanent perturbation of normal receptor processes and transmitter activity within synapses of specific structures of the limbic system. This theory thus explains the nature of the rewarding properties of alcohol as well as its complex addictive liability which is physiologically irreversible.

We have previously reported that UChA rats (genetically low ethanol consumer) develop tolerance to narcosis time easier than UChB rats (genetically high ethanol consumer). We also have reported that UChA rats develop tolerance to the hypothermic effect of ethanol, while in UChB rats the repeated administration of ethanol induces sensitization towards this effect. In the present paper the effects of alpha-methyl-p-tyrosine (AMPT)--a competitive inhibitor of norepinephrine synthesis--on ethanol-induced narcosis and hypothermia, as well as in the development of tolerance to these effects, were studied in both strains of rats. Results obtained show that AMPT pretreatment induced a significantly higher increase in narcosis time and hypothermia, as well as, greater susceptibility to ethanol toxicity in UChB than UChA rats. Furthermore, the simultaneous treatment with AMPT and ethanol did not change the development of tolerance to narcosis time in both strains and to hypothermia and sensitization in UChA and UChB rats respectively.

Using rats which are self-administering ethanol in an operant situation, we have tested a variety of agonists and antagonists in an attempt to determine the role various CNS neurotransmitters may play in ethanol drinking. The major emphasis of the work has been on the dopaminergic and the benzodiazepinergic systems. This paper reviews prior work and provides new data on additional agonists and antagonists. The data suggest a possible reciprocal interaction between dopamine and benzodiazepine brain systems. This hypothesis is based on the change in pattern of lever responding which results when various agonists, antagonists and inverse agonists related to these neurotransmitters are compared. That is, similar changes in response pattern are found for dopamine agonists and benzodiazepine inverse agonists. On the other hand, dopamine antagonists and benzodiazepine agonists are similar to each other and produce a different set of changes. A neural circuit for a reciprocal interaction between the ventral tegmentum and the nucleus accumbens is proposed as one possible pathway which may be involved in these observations.

This paper reviews five separate experimental studies concerning the acute or chronic effects of alcohol on late ERP components related to cognitive processes. The studies are evaluated for their adequacy in two arenas: (a) task relevance from a behavioral viewpoint, and (b) their ability to clarify the functional significance of alcohol-related ERP changes. Based upon the general trends of the results reported from the five individual laboratories conducting the investigations, it can be concluded that the P3 component is the most consistently altered of the four late ERP components considered (N1, N2, P2, P3). The finding of a reduced P3 amplitude was more reliable than the finding of increased P3 latency. Alterations in ERP components, when they did occur, occurred under the acute influence of ethanol, as well as in abstinent chronic alcoholics. All of the ERP findings reported were obtained using variations of signal detection procedures. Changes in ERP components did not always parallel performance changes, suggesting that aspects of psychological processes (e.g., attention and stimulus evaluation), presumed to underly ERPs' functional significance, did not directly reflect these processes.

This paper suggests that like ethanol, methanol also produces certain changes in the steady state level of monoamines in hypothalamus and striatum of albino rats. Though, the toxic manifestations of methanol are attributed to the metabolic end product of methanol viz. formic acid by several workers, we report here that the methanol-induced brain monoamine changes, at least, could be attributed to the direct action of methanol rather than to its metabolic end products like formaldehyde or formate. Studies in the steady state level of rat brain monoamines have shown that after methanol administration (3 g/kg), there is severe depletion of dopamine level in striatum but a significant increase in the level of dopamine, serotonin and 5-hydroxy indole acetic acid in hypothalamus. At the same time, norepinephrine and epinephrine levels are reduced in hypothalamus as well as in striatum. These effects do not seem to be induced by metabolic acidosis. The changes in monoamine levels are very well correlated with the blood and brain level of methanol as evidenced by maintaining a higher methanol level either by simultaneous administration of ethanol or by blocking methanol metabolism by pretreatment with 4-methyl pyrazole and 3-amino-1,2,4-triazole. It is thus postulated that monoamine changes induced by methanol appear to be the direct effect of methanol per se on the monoaminergic neuronal membranes.

The biochemical consequences of moderate chronic ethanol ingestion has been scarcely investigated in spite of the fact that most of the human population drinks ethanol on a moderate basis. This paper describes some metabolic effects produced by moderate ethanol consumption. The substitution of drinking water in rats for a 10% ethanol solution during 4 weeks resulted in: a) a decrease of blood urea and citrulline synthesis in liver mitochondria; b) a slight inhibition in state 3 and state 4 respiration either with glutamate-malate as substrates or succinate as substrate; c) no change in ADP/O ratio with succinate but slight increase with glutamate-malate; d) a reduction of the cytochrome oxidase activity and cytochromes a+a3 content; e) a 42% increase in the succinate dehydrogenase activity and a small but constant increase in the Vmax (no change in the Km) of the adenine nucleotide translocase activity in liver mitochondria. These results show that even moderate, but continuous ethanol ingestion, produces metabolic responses that must be carefully evaluated to define health risk in larger human groups.

This paper reviews the potential health risks for persons who consume the newly available "non-alcoholic" or "de-alcoholized" beverages which may contain trace amounts of ethanol (less than 0.5% by volume). The discussion includes relative risk rates for chemical dependency, fetal alcohol syndrome, chemical and natural hypersensitivity, cancer, cardiomyopathy, hypertension and cirrhosis for those who drink standard alcoholic drinks and "non-alcoholic" drinks. It is concluded that non-alcoholic drinks pose little risk for developing alcohol related problems based on our current physiological and psychocultural knowledge.

This paper suggests that the strategy of studying individuals at high risk to develop alcoholism by comparing, for example, sons of alcoholic fathers with sons of nonalcoholic fathers might not control for handedness or for patterns of cerebral laterality. In our sample of alcoholic men, at least 50% of the men left-handed or having a left-handed first-degree relative had an alcoholic father, versus only 26% of the right-handed men not having a left-handed first-degree relative. If generalized to nonalcoholic individuals, these data suggest that a larger proportion of the sons of alcoholic fathers either would be left-handed or would have a left-handed first-degree relative, and might have an anomalous pattern of cerebral dominance. Furthermore, several findings associated with being at high risk for alcoholism have also been associated with left-handedness or with left-hemisphere dysfunction.

State and local legal provisions have a major impact on a community's drinking patterns in licensed drinking establishments. State Alcoholic Beverage Control (ABC) laws regulate how many (if any) bars are permissible in a given locale; set standards for management practice; set limitations on location and design; establish who may have ownership interests; and establish price guidelines, either directly through price maintenance statutes or indirectly through excise tax policy. State law may also hold bar owners liable for injuries caused by their drunk or underaged patrons to members of the general public ("dram shop" laws and case decisions). This paper reviews the scope and character of these legal provisions, discusses their potential role in preventing alcohol-related problems, and analyzes the inadequacy of most existing bar studies for developing public health policy measures. It concludes with a discussion of a prevention strategy ("server intervention") and an agenda for future research studies.

Previous work with the serotonin uptake blocker, sertraline, demonstrated that the drug suppressed the consumption of ethanol and saccharin as well as body weight gain. There is increasing evidence that many serotonergic agents such as agonists, releasing agents and uptake blockers, reduce food intake. Sertraline was found to have a robust anorexic action. In this paper evidence is presented which supports the hypothesis that the administration of serotonin uptake blockers reduce ethanol consumption as a secondary consequence of a suppression in food intake.

The importance of genotypic differences in the determination of sensitivity to ethanol, tolerance development and physical dependence susceptibility is achieving ever greater recognition. It is now generally accepted by investigators studying the biochemical and physiological bases for alcoholism that genotype can influence all these different aspects of sensitivity to the effects of ethanol. Although there is convincing evidence that susceptibility to alcoholism is inherited in man, we have no idea what it is that is inherited [2, 7, 19, 24, 31]. By examining a family history for a particular individual, we can identify individuals at familial risk for developing problems with alcohol abuse. However, environmental as well as genetic factors are important in determining who does and who does not become an alcoholic [4]. Thus, one critical need is for a genetic marker for alcoholism. Since the search for such markers in human research is both expensive and time-consuming, this has led to the use of animal models for alcoholism. Animal models are particularly helpful for genetic research since their genetics are well understood and can be specifically tooled to the task at hand. The goal of this paper is to illustrate the principal genetic methodologies that have been employed to study the human and animal pharmacogenetics of alcohol, and to identify future directions in this area.