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Alcoholism and alcohol abuse represent a significant medical and societal problem, and have been thoroughly investigated in humans as well as using animal models. A less well understood aspect of alcohol related disorders is the possible effect of this drug on offspring whose parents were exposed prior to conception. The zebrafish has been successfully employed in alcohol research, however, the effect of exposing the parents to alcohol before fertilization of the eggs on offspring has not been demonstrated in this species. In this proof of concept study, we attempt to address this hiatus. We exposed both adult male and female zebrafish to 0.0% (control) or 0.5% (vol/vol) alcohol chronically for 7 days, subsequently bred the fish within their respective treatment group, collected the fertilized eggs, allowed them to develop, and tested the behavior of free-swimming offspring at their age of 7-9 days post-fertilization. We conducted the analysis in two genetically distinct quasi-inbred strains of zebrafish, AB and TL. Although gross morphology and general activity of the fish appeared unaffected, we found significant behavioral alterations in offspring of alcohol exposed parents compared to offspring of control parents in both strains. These alterations included robustly increased duration and reduced frequency of immobility, increased turn angle, and increased intra-individual variance of turn angle in offspring of alcohol exposed parents in both strains. The mechanisms underlying these behavioral effects or whether the effects are due to exposure of the father, the mother, or both to alcohol are unknown. Nevertheless, our results now set the stage for future studies with zebrafish that will address these questions.

Abstract 1. 1. For three groups of rats, intraperitoneal injections of either 250, 500, or 1000 mg/kg ethanol were paired with a distinctive environment and later a choice was offered between that environment and one that had previously been associated with saline injections. 2. 2. For a second set of three groups of animals the identical procedure was followed except that food was available in both the environment paired with ethanol and the one paired with saline. 3. 3. The rats showed no preference or aversion for the environment paired with the 250 mg/kg dose either when the drug was given alone or when combined with the availability of food. No preference or aversion for the 500 mg/kg dose was indicated when the drug was given alone, but the same dose combined with food was preferred to food plus saline. The 1000 mg/kg dose was found to be aversive when given by itself, yet the same dose was neither aversive nor preferred when combined with the availability of food. 4. 4. These findings suggest that ethanol can interact with food, a positive reinforcer, in ways that cannot be predicted from the effect of the drug when presented alone.

AbstractAimsTo examine how standard analytical approaches to model mortality outcomes of alcohol use compare to the true results using the impact of the March 2017 alcohol taxation increase in Lithuania on all-cause mortality as an example.MethodsFour methodologies were used: two direct methodologies: (a) interrupted time-series on mortality and (b) comparing predictions based on time-series modeling with the real number of deaths for the year following the implementation of the tax increase; and two indirect methodologies: (c) combining a regression-based estimate for the impact of taxation on alcohol consumption with attributable-fraction methodology and (d) using price elasticities from meta-analyses to estimate the impact on alcohol consumption before applying attributable-fraction methodology.Results and ConclusionsWhile all methodologies estimated reductions in all-cause mortality, especially for men, there was substantial variability in the level of mortality reductions predicted. The indirect methodologies had lower predictions as the meta-analyses on elasticities and risk relations seem to underestimate the true values for Lithuania. Directly estimated effects of taxation based on the actual mortalities seem to best represent the true reductions in alcohol-attributable mortality. A significant increase in alcohol excise taxation had a marked impact on all-cause mortality in Lithuania.

It is not known why some heavy-drinking women give birth to children with alcohol-related birth defects (ARBD) whereas others do not. The objective of this study was to determine whether the frequency of elevated maternal blood acetaldehyde levels among alcoholics is in the range of ARBD among alcoholic women. MEDLINE was searched from 1980 to 2000 using the key words acetaldehyde, pharmacokinetics, and alcoholism for controlled trials reporting blood or breath acetaldehyde levels in alcoholics and nonalcoholics. Separately, using the key words fetal alcohol syndrome, epidemiology, prevalence, incidence, and frequency, articles were identified reporting ARBD incidences among the offspring of heavy drinkers. Of 23 articles reporting acetaldehyde levels in alcoholics, four met the inclusion criteria. Forty-three studies reported on the rate of ARBD in heavy drinkers, and 14 were accepted. Thirty-four percent of heavy drinkers had a child with ARBD, and 43% of chronic alcoholics had high acetaldehyde levels. The similar frequencies of high acetaldehyde levels among alcoholics and the rates of ARBD among alcoholic women provide epidemiologic support to the hypothesis that acetaldehyde may play a major role in the cause of ARBD.

Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423

Zebrafish have become a popular animal model for studying the development of alcohol addiction. Several behavioral paradigms for studying alcohol addiction have been developed for zebrafish, including conditioned place preference, alcohol-induced tolerance, and withdrawal. However, alcohol choice preference tasks have not been established in zebrafish as of yet. The ability of zebrafish to detect alcohol in their environment is required in alcohol choice or preference tasks. To our knowledge, it is currently unknown whether zebrafish are able to detect alcohol in their environment immediately following bath immersion. In the current study, we analyzed the time course of alcohol-induced behavioral changes of zebrafish while being immersed in alcohol solution in a 1.5 L tank. We recorded each trial in high-definition and quantified behavioral responses using automated video tracking-based and manual observation-based methods to quantify temporal changes in alcohol-induced behaviors. As alcohol is known to require several minutes of bath immersion to reach the brain in zebrafish, we argued that behavioral responses before this time point would prove zebrafish's ability to detect this substance in the water. Our results show that a 60-min exposure to 1% alcohol alters behavioral responses in a time-dependent manner. Notably, alcohol exposure significantly increased absolute turn angle, decreased distance to bottom, and variance of distance to bottom within the first 3 min immediately following exposure, a response that occurred before alcohol could reach the brain of the subjects in measurable amounts. These results imply that zebrafish are able to detect alcohol in their environment immediately following immersion into the drug solution.

Alcohol and nicotine (in the form of tobacco) are often taken together, with increased negative health consequences. Co-use may modify intake of one or both of the drugs, or the effects of drugs used to treat nicotine or alcohol addiction. Varenicline is commonly prescribed as an aid to enhance quitting smoking. More recently it has been shown to reduce alcohol intake in humans and laboratory animals. There is little work investigating the role of co-exposure to alcohol and nicotine in the effects of varenicline. In pilot clinical studies, it has been reported that smoking enhances varenicline's effectiveness as a treatment for alcohol misuse, but this relationship has not been systematically investigated. To help resolve this, we examined if the effects of varenicline on alcohol and nicotine self-administration (SA) in rats are modified when the two drugs are taken together. Rats were trained on alcohol SA, and some were implanted with i.v. catheters for nicotine SA. Groups of animals then lever pressed for alcohol or nicotine alone, and another group lever pressed for alcohol and nicotine, using a two lever choice procedure. Varenicline did not affect alcohol SA. Varenicline reduced nicotine SA modestly. Access to both alcohol and nicotine reduced self-administration of either drug, but did not change the effects of varenicline. We found that in rats with a history of alcohol SA, varenicline reduced reinstatement of extinguished alcohol seeking induced by exposure to an alcohol prime combined with cues previously associated with alcohol.