Alcoholism, clinical and experimental research最新文献

Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABA_A and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized.

Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABA_A ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.).

Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABA_A and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED₅₀ : 0.017 mg/kg) > midazolam (ED₅₀ : 1.6 mg/kg) > pentobarbital (ED₅₀ : 3.7 mg/kg) > EtOH (ED₅₀ : 700 mg/kg, or 0.7 g/kg) in these subjects.

Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.

Background: Self-Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse.

Methods: To identify candidate genes with a role in SRE and alcohol-related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster. We first performed a gene-based analysis of Genomewide association studies (GWAS) summary statistics for SRE in the Avon Longitudinal Study of Parents and Children sample. Based on prior findings in humans, orthology to fly genes, and the availability of genetic reagents, we selected a subset of these genes for studies on EtOH behavior in Drosophila.

Results: We found 37 genes with nominal associations in our SRE GWAS. We explored the role of 6 orthologous genes in Drosophila EtOH sedation and rapid tolerance. We found that the transcription factor Mef2 is required for normal EtOH sedation in flies. Pan-neuronal expression of 2 independent Mef2 RNAi transgenes significantly reduced Mef2 expression and made flies resistant to EtOH sedation. Additionally, flies with multiple independent mutant alleles of Mef2 were also resistant to EtOH sedation, confirming a role for Mef2 in this behavior. Altered expression of Mef2 did not change EtOH rapid tolerance or cause a net change in internal EtOH concentrations.

Conclusions: Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila.

Background: Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms. Alcohol's metabolites induce DNA damage, an early step in carcinogenesis. We assessed the effect of time of alcohol consumption on markers of tissue damage in the colonic epithelium.

Methods: Mice were treated by alcohol or phosphate-buffered saline (PBS), at 4-hour intervals for 3 days, and their colons were analyzed for (i) proliferation (Ki67) and antiapoptosis (Bcl-2) markers, (ii) DNA damage (γ-H2AX), and (iii) the major acetaldehyde (AcH)-DNA adduct, N² -ethylidene-dG. To model circadian disruption, mice were shifted once weekly for 12 h and then were sacrificed at 4-hour intervals. Samples of mice with a dysfunctional molecular clock were analyzed. The dynamics of DNA damage repair from AcH treatment as well as role of xeroderma pigmentosum, complementation group A (XPA) in their repair were studied in vitro.

Results: Proliferation and survival of colonic epithelium have daily rhythmicity. Alcohol induced colonic epithelium proliferation in a time-dependent manner, with a stronger effect during the light/rest period. Alcohol-associated DNA damage also occurred more when alcohol was given at light. Levels of DNA adduct did not vary by time, suggesting rather lower repair efficiency during the light versus dark. XPA gene expression, a key excision repair gene, was time-dependent, peaking at the beginning of the dark. XPA knockout colon epithelial cells were inefficient in repair of the DNA damage induced by alcohol's metabolite.

Conclusions: Time of day of alcohol intake may be an important determinant of colon tissue damage and carcinogenicity.

Background: Impairment of monocarboxylate transporter (MCT)-dependent astrocyte-neuron lactate transfer disrupts long-term memory and erases drug-associated memories in mice. However, few studies have examined how drugs of abuse alter astrocyte-neuron lactate transfer in neurocircuits related to addiction. This is particularly pertinent for ethanol (EtOH), which has been demonstrated to impair central nervious system (CNS) glucose uptake and significantly alter peripheral levels of glucose, lactate, acetate, and ketones.

Methods: We subjected C57BL/6J mice to a chronic intermittent EtOH (CIE) exposure paradigm to investigate how chronic EtOH exposure alters the concentration of glucose and lactate within the serum and CNS during withdrawal. Next, we determine how chronic injections of lactate (1 g/kg, twice daily for 2 weeks) influence central and peripheral glucose and lactate concentrations. Finally, we determine how CIE and chronic lactate injection affect astrocyte-neuron lactate transfer by analyzing the expression of MCTs.

Results: Our results show that CIE induces lasting changes in CNS glucose and lactate concentrations, accompanied by increased expression of MCTs. Interestingly, although chronic lactate injection mimics the effect of EtOH on CNS metabolites, chronic lactate injection is not associated with increased expression of MCTs.

Conclusion: CIE increases CNS concentrations of glucose and lactate and augments the expression of MCTs. Although we found that chronic lactate injection mimics EtOH-induced increases in CNS lactate and glucose, lactate failed to alter the expression of MCTs. This suggests that although lactate may influence the homeostasis of bioenergetic molecules in the CNS, EtOH-associated increases in lactate are not responsible for increased MCT expression.

Background: Rates of high-intensity drinking, which is alcohol consumption that exceeds standard heavy drinking levels, have increased in recent years and peak in young adulthood. To identify modifiable environmental targets for prevention of high-intensity drinking, we identified characteristics of parties attended by youth and young adults that were associated with high-intensity drinking and the consequences of this excessive form of drinking.

Methods: Data are from 15- to 20-year-old participants in an online survey (n = 2,442; 55.4% female, 74.8% White) who resided in 24 communities across 7 states that were a part of a community randomized intervention trial to reduce the incidence and consequences of underage drinking parties. We used multinomial logistic regression to predict level of drinking by 6 party characteristics (size, location, age and gender composition, supervision, others' drinking behavior), and to predict 6 consequences (hangover, not remember event, passed out, punished by parents, broke something/got in fight, and sex against will) from level of drinking. We tested study hypotheses in 2 models, one that used a single binge drinking threshold (below binge vs. at or above binge level) and one that additionally used a high-intensity drinking level (below binge, 1 to 2 times binge, 2+ times binge level).

Results: We found that larger party size and a mostly male composition were unique predictors of high-intensity drinking when compared to those who consumed 1 to 2 times the binge drinking level. Odds of passing out, not remembering the drinking event, breaking/damaging property, or getting in a fight were more than double for high-intensity drinkers compared to standard binge level drinkers.

Conclusions: Results from this study indicate there are unique precursors and consequences of high-intensity alcohol consumption among youth and young adults. These environmental factors associated with high-risk drinking contexts can be used to develop prevention strategies to mitigate the harms associated with excessive alcohol consumption.

Background: Previous neuroimaging studies examining relations between alcohol misuse and cortical thickness have revealed that increased drinking quantity and alcohol-related problems are associated with thinner cortex. Although conflicting regional effects are often observed, associations are generally localized to frontal regions (e.g., dorsolateral prefrontal cortex [DLPFC], inferior frontal gyrus [IFG], and anterior cingulate cortex). Inconsistent findings may be attributed to methodological differences, modest sample sizes, and limited consideration of sex differences.

Methods: This study examined neuroanatomical correlates of drinking quantity and heavy episodic drinking in a large sample of younger adults (N = 706; M_age  = 28.8; 51% female) using magnetic resonance imaging data from the Human Connectome Project. Exploratory analyses examined neuroanatomical correlates of executive function (flanker task) and working memory (list sorting).

Results: Hierarchical linear regression models (controlling for age, sex, education, income, smoking, drug use, twin status, and intracranial volume) revealed significant inverse associations between drinks in past week and frequency of heavy drinking and cortical thickness in a majority of regions examined. The largest effect sizes were found for frontal regions (DLPFC, IFG, and the precentral gyrus). Follow-up regression models revealed that the left DLPFC was uniquely associated with both drinking variables. Sex differences were also observed, with significant effects largely specific to men.

Conclusions: This study adds to the understanding of brain correlates of alcohol use in a large, gender-balanced sample of younger adults. Although the cross-sectional methodology precludes causal inferences, these findings provide a foundation for rigorous hypothesis testing in future longitudinal investigations.