Low Alcohol Sensitivity Research Articles

Association Between GABRG2 and Self-Rating of the Effects of Alcohol in a French Young Adult Sample.

Alcohol use is a leading risk factor for preventable death, injury, and disease globally. Low sensitivity to the effects of alcohol is influenced by genes and predicts risk for harmful alcohol use and alcohol use disorder (AUD). Alcohol induces effects partly by modulation of gamma-aminobutyric acid receptors type A (GABAARs). This study investigates the relationship between genetic variation in GABAAR subunit genes and individual alcohol sensitivity among French university students. The study involved 1,409 French university students (34.5% women; mean age 20.3 years). Alcohol sensitivity was measured by the Self-Rating of the Effects of Alcohol Scale (SRE). SRE-scores from initial drinking, regular drinking, and heavy drinking were investigated for correlations with alcohol consumption and for associations with single nucleotide polymorphisms (SNPs) in GABAAR subunit genes (GABRA2, GABRG2, GABRA6). We replicated correlations between low alcohol sensitivity and high alcohol consumption. We further found an association between the minor allele in rs211014 (GABRG2) and higher SRE-scores, linked to dizziness and motor incoordination. Genetic variation in GABRG2 has previously been associated with processes involving motor coordination (alcohol withdrawal, febrile- and epileptic seizures). The results from our study suggest that genetic variation in GABRG2 may influence alcohol sensitivity, which could inform strategies for assessing risk for harmful alcohol use and AUD.

Drinking motives and alcohol sensitivity mediate multi-dimensional genetic influences on alcohol use behaviors.

Genetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. Using results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs. In univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while BeerPref PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of BeerPref PGS on all AUBs via the joint effect of mediators including alcohol sensitivity. These findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

Alcohol craving in the natural environment: Moderating roles of cue exposure, drinking, and alcohol sensitivity.

Effects of cue exposure and alcohol consumption (e.g., priming doses) on craving for alcohol have been examined in largely separate literature, limiting what is known about their potential interaction. Individuals with low alcohol sensitivity, a known risk factor for alcohol use disorder (AUD), exhibit stronger cue-elicited craving than their higher-sensitivity (HS) peers in both laboratory and real-world contexts. Here, underage drinkers (N = 155) completed a 21-day ecological momentary assessment (EMA) protocol in which they recorded exposure to alcohol cues and levels of craving during both nondrinking and postdrinking moments. Multilevel modeling detected a significant interaction of cue exposure and postdrinking status on craving. Cue-induced craving was increased in postdrinking moments compared to nondrinking moments. Contrary to prediction, cue-elicited increase in craving during nondrinking moments was stronger in participants reporting higher sensitivity to alcohol. In the presence of cues, lower sensitivity was robustly related to craving intensity in the postdrinking state but unrelated to craving during nondrinking moments. Craving during drinking episodes in the natural environment is magnified by the presence of alcohol cues, potentially contributing to the maintenance or acceleration of drinking episodes. Moreover, lower-sensitivity drinkers may be particularly susceptible to the combined effects of cue exposure and postdrinking status on alcohol craving. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of alcohol sensitivity on alcohol-induced blackouts and passing out: An examination of the alcohol sensitivity questionnaire among underage drinkers.

The role of alcohol sensitivity in the experience of blacking out and passing out has not been well established. Here, we examined the relation between individual differences in alcohol sensitivity (i.e., numbers of drinks required to experience various effects of alcohol) and reports of blacking out and passing out in the past year. Participants (925 healthy, underage college student drinkers) completed the Alcohol Sensitivity Questionnaire (ASQ) and reported on their past year blacking out and passing out experiences. The fit of the ASQ's 2-factor structure was fair (CFI=0.90, RMSEA=0.09) in this sample of underage drinkers. In unadjusted models, higher ASQ scores (i.e., requiring more drinks to experience effects, indicating lower alcohol sensitivity) were associated with experiencing more blackouts (IRR=1.68 [1.31-2.15]) and passing out (IRR=2.25 [1.59-3.18]) in the past year. After controlling for typical consumption, however, higher ASQ scores were associated with fewer past-year blackouts (IRR=0.76 [0.60-0.98]). Total ASQ scores moderated the relationship between typical alcohol consumption and blackout occurrence (interaction IRR=0.96 [0.93-0.98]), but not passing out occurrence (interaction IRR=0.95 [0.89-1.01]), with the quantity of alcohol consumed more strongly associated with blackout occurrence among higher-sensitivity than lower-sensitivity drinkers. These findings are consistent with prior work suggesting that low sensitivity may act as a paradoxical risk factor for certain heavy drinking effects, contributing to higher levels of alcohol consumption and more frequent negative consequences while also conferring protection (relative to high-sensitivity peers) at a given level of alcohol exposure.

Transfer of incentive salience from a first-order alcohol cue to a novel second-order alcohol cue among individuals at risk for alcohol use disorder: electrophysiological evidence.

In susceptible individuals, cues associated with drug use are theorized to take on incentive-motivational properties, including the ability to reinforce higher-order, drug-related associative learning. This study aimed to test this prediction among people varying in risk for alcohol use disorder. Repeated-measures experiment with a measured individual difference variable at a University psychology laboratory in Missouri, USA. One hundred and six young adults (96 contributed complete data) were pre-selected to represent the upper and lower quartiles of self-reported sensitivity to alcohol's acute effects. Participants completed a second-order Pavlovian conditioning paradigm in which an initially neutral visual cue (second-order conditional stimulus; CS2 ) predicted onset of an olfactory cue (first-order conditional stimulus; CS1 ). Olfactory cues were isolated from alcoholic beverages, sweets and non-comestible substances, each presumed to have a natural history of first-order conditioning. Event-related potential responses to the CS2 across its conditioning and extinction, and to the CS1 , provided neurophysiological indices of incentive salience (IS). The IS of the alcohol CS1 was higher among participants low in alcohol sensitivity (LS), relative to their higher-sensitivity (HS) peers. The IS of the CS2 paired with the alcohol CS1 increased across the CS2 conditioning phase among LS but not HS participants. Also, LS (but not HS) individuals also experienced increases in alcohol craving following alcohol CS1 exposure, and this change was correlated with increases in the IS of the CS2 paired with the alcohol CS1 . Alcoholic beverage odor, a proximal cue for alcohol consumption, appears to reinforce conditioning of neurophysiological responses to a novel cue among low alcohol sensitivity (LS) individuals but not high alcohol sensitivity individuals, providing the first evidence that the LS phenotype may be associated with differences in the conditioned reinforcing properties of alcohol-related cues. These findings support the idea that the LS phenotype may increase alcohol use disorder risk via susceptibility to incentive salience sensitization.

The Prospective Association of Negative Urgency With Hazardous Drinking Via Impaired Control: A Moderating Role of Alcohol Sensitivity

Trait negative urgency is consistently associated with alcohol problems, and cross-sectional findings have suggested a mediational role of impaired control over alcohol. Initial evidence also suggests that individual differences in self-reported sensitivity to alcohol's effects may moderate the association between urgency and alcohol outcomes. The aim of this study was to replicate and extend these findings using prospective data. Young adult drinkers (N = 159, mean age = 18.87, SD = 1.16; 70.4% female) from Montreal, Quebec, Canada, completed an online survey at baseline and again 6 months later. Participants completed questionnaires measuring negative urgency, alcohol sensitivity, impaired control over alcohol, and hazardous drinking. Moderated mediation analyses revealed that the prospective indirect association between negative urgency at baseline and hazardous drinking at follow-up (mediated via increased impaired control at follow-up) was significant only for young adults who reported relatively lower alcohol sensitivity at baseline. Using prospective data from a unique sample of young adults, the present study partially replicates prior cross-sectional findings suggesting that the indirect association between urgency and hazardous drinking via impaired control over alcohol is moderated by alcohol sensitivity.

Interactive Effects of Naturalistic Drinking Context and Alcohol Sensitivity on Neural Alcohol Cue-Reactivity Responses.

Considerable evidence indicates that a low level of subjective response to alcohol's acute effects (i.e., low sensitivity) is associated with enhanced risk for alcohol use disorder (AUD). Recent work suggests that the highest risk response profile consists of blunted sensitivity to alcohol's sedation-like effects, coupled with enhanced sensitivity to alcohol's stimulation-like effects (i.e., differential sensitivity). A largely separate body of work indicates that enhanced reactivity to alcohol-related cues is associated with increased AUD risk. The current research examined the extent to which variability in alcohol response phenotypes is associated with enhanced P3 event-related potential (ERP) responses to alcohol-related pictures (ACR-P3), and whether this reactivity varies according to depicted drinking contexts. Eighty young adults (aged 18 to 33years) completed a self-report measure of alcohol sensitivity (the Alcohol Sensitivity Questionnaire) and viewed images depicting drinking in naturalistic contexts, alcohol and nonalcohol beverages in isolation (devoid of naturalistic drinking context), and neutral nonbeverage control images while ERPs were recorded. Results indicated that blunted sensitivity to alcohol's sedative-like effects was differentially associated with enhanced ACR-P3 but reduced P3 reactivity to nonalcohol cues. Variation in sensitivity to alcohol's stimulant-like effects was not associated with differential ACR-P3. Contrary to predictions, these effects were not potentiated by drinking contexts. The current results replicate and extend previous work linking low alcohol sensitivity with enhanced incentive salience for alcohol-related cues and suggest that cues depicting drinking contexts are less likely to differentiate high-risk from low-risk drinkers.

SA114 - GENETIC ETIOLOGY OF SELF-RATING OF THE EFFECTS OF ALCOHOL (SRE) SCORES IN YOUNG ADULTS

Background Alcohol misuse is a significant public health concern with social, medical, and economic consequences. Previous studies suggest that initial sensitivity to alcohol may impact use of the substance: those with low sensitivity may drink more, potentially establishing unhealthy drinking habits that persist into adulthood. The Self-Rating of the Effects of Alcohol (SRE) scale was developed to quantify initial sensitivity to alcohol, and SRE scores have been positively associated with concurrent and later drinking behaviors. Furthermore, evidence suggests that SRE scores are influenced by familial factors, raising the possibility that genetic liability to low alcohol sensitivity may increase risk of later alcohol misuse. We sought to clarify the role of genetic factors on SRE scores in two samples of young adults. Methods We derived SRE scores in two population-based cohort studies. ALSPAC participants were born between 1991–1992 in the southwest region of England and have been assessed at least once per year since birth. SRE scores were derived based on assessments at ages 15.5, 16.5, and 17.5. S4S participants were students at a large, public, urban university in the southeastern US, enrolled during the fall or spring of their freshman year (2011–2013), and assessed each subsequent spring. Participants were of diverse ancestry and were 18+ years of age at initial enrollment. The first available SRE score was used for subsequent analyses. Phenotypic and genotypic data meeting all quality control filters were available for a total of N=7339 participants. We conducted Genome-Wide Association Studies (GWAS) within each sample/ancestry group, using ancestry-informative principal components, sex, and age at first available SRE assessment as covariates. Initial GWAS results were meta-analyzed in METAL. SNP-based heritabilities for each sample/ancestry group were estimated in GCTA. Additional secondary analyses were conducted in VEGAS and JEPEGMIX2. Results A total of 15,642,250 markers were analyzed in at least one group. No individual marker met genome-wide significance criteria. The top marker, rs146298733 (p=3.16e-07), mapped to an intron in DLGAP1, variants in which have been previously associated with psychiatric outcomes including major depression and obsessive-compulsive disorder. Meta-analysis of GCTA results indicated that SRE is modestly heritable (h2SNP=0.19, SE=0.10), though this was driven primarily by the ALSPAC sample, for which assessments were prospective. Pathway analyses implicated the GABAergic system and genes related to thromboxane signaling, both of which have been associated with alcohol-related phenotypes. Discussion We present evidence consistent with prior reports that initial sensitivity to alcohol is influenced by genetic factors. Preliminary analyses implicate systems known to influence other alcohol phenotypes and provide novel targets for future analysis. Implicated loci and aggregate genetic risk should be confirmed in independent samples. Heterogeneity across samples suggests that assessment methods are important to SRE measurement, which may have implications for genetic analyses. Further characterization of genetic influences may elucidate mechanisms underlying the pathway from initial sensitivity to alcohol problems.

P3 event-related potential reactivity to smoking cues: Relations with craving, tobacco dependence, and alcohol sensitivity in young adult smokers.

The current study tested whether the amplitude of the P3 event-related potential (ERP) elicited by smoking cues is (a) associated with the degree of self-reported craving reactivity, and (b) moderated by degree of tobacco dependence. Because alcohol and cigarettes are frequently used together, and given recent evidence indicating that individual differences in alcohol sensitivity influence reactivity to alcohol cues, we also investigated whether alcohol sensitivity moderated neural responses to smoking cues. ERPs were recorded from young adult smokers (N = 90) while they participated in an evaluative categorization oddball task involving 3 types of targets: neutral images, smoking-related images, and images of drinking straws. Participants showing larger P3 amplitudes to smoking cues and to straw cues (relative to neutral targets) reported greater increases in craving after cue exposure. Neither smoking status (daily vs. occasional use) nor psychometric measures of tobacco dependence consistently or specifically moderated P3 reactivity to smoking cues. Lower alcohol sensitivity was associated with larger P3 to smoking cues but not comparison straw cues (relative to neutral targets). This effect was further moderated by tobacco dependence, with the combination of lower sensitivity and higher dependence associated with especially pronounced P3 reactivity to smoking cues. The findings suggest the smoking-cue elicited P3 ERP component indexes an approach-oriented incentive motivational state accompanied by a subjective sense of cigarette craving. Self-reported low sensitivity to the pharmacologic effects of alcohol may represent a marker of drug cue reactivity and therefore deserves attention as a potential moderator in smoking cue exposure studies. (PsycINFO Database Record

The natural expression of individual differences in self-reported level of response to alcohol during ecologically assessed drinking episodes.

Low sensitivity to alcohol is a well-established risk factor for alcohol use disorder (AUD). However, little is known about how the low sensitivity phenotype is expressed on a fine-grained, momentary level in drinkers' daily experience. The objective of the study is to evaluate individual differences in subjective states and appraisals of alcoholic beverages during the ascending limb of real-world drinking episodes. Social drinkers (N = 398) with varying degrees of alcohol sensitivity as indexed by the Self-Rating of the Effects of Alcohol form (SRE; Schuckit et al. in Addiction 92:979-988, 1997a) recorded diary entries over a 3-week monitoring period (2576 drinking episodes containing 6546 moments). Hierarchical linear modeling was used to evaluate whether individual differences in alcohol sensitivity predicted differing intra-episode estimated blood alcohol concentration (eBAC) trajectories, ratings of subjective states, and drink appraisals. Lower self-reported alcohol sensitivity was associated with consuming "too much, too fast," as indicated by a steeper slope of ascending eBAC. In models adjusted for momentary eBAC level, participants reporting lower alcohol sensitivity at baseline showed blunted subjective intoxication and drink-contingent punishment. The results suggest that low sensitivity to alcohol is associated with a blunting of some forms of subjective feedback (i.e., perceptions of intoxication and punishment) that might typically encourage drinking restraint. This may 'tip the scales' toward excess consumption and could help to explain why a low alcohol sensitivity forecasts AUD.

Gingival condition and tooth‐brushing behavior after alcohol consumption

Various studies have reported the relationship between alcohol consumption and gingival condition. However, they focus on the direct effects of alcohol consumption or alcohol sensitivity on gingival condition, and it is unclear how oral health behaviors relate these relationships. The aims of this study were to assess the inter-relationships between gingival condition, tooth-brushing behavior after drinking alcohol and alcohol sensitivity in university students who drink more than once per week on average. A total of 808 students (541 males, 267 females) that habitually consume alcohol were analyzed. The disease activity of gingival condition was assessed as the percentage of bleeding on probing (%BOP). Additional information regarding alcohol sensitivity and oral health behaviors, including tooth-brushing behavior after drinking, were also collected. Thirteen percent of the current participants reported neglecting tooth-brushing after drinking, and their alcohol consumption was higher than those who did not neglect tooth-brushing. Logistic regression analysis showed that high %BOP (%BOP ≥ 20) was associated with male (OR = 1.53; 95% CI, 1.01-2.33), neglect of tooth-brushing after drinking (OR = 2.60; 95% CI, 1.20-5.61) and debris index (OR = 8.38; 95% CI, 4.24-16.60) in participants with low alcohol sensitivity. In participants with high alcohol sensitivity, high %BOP was associated with debris index (OR = 7.60; 95% CI, 3.12-18.51), but not with any oral health behaviors. The study revealed that alcohol consumption was indirectly related to gingival disease activity through the neglect of tooth-brushing after drinking alcohol in university students with low alcohol sensitivity.

Transient overexpression of adh8a increases allyl alcohol toxicity in zebrafish embryos.

Fish embryos are widely used as an alternative model to study toxicity in vertebrates. Due to their complexity, embryos are believed to more resemble an adult organism than in vitro cellular models. However, concerns have been raised with respect to the embryo's metabolic capacity. We recently identified allyl alcohol, an industrial chemical, to be several orders of magnitude less toxic to zebrafish embryo than to adult zebrafish (embryo LC50 = 478 mg/L vs. fish LC50 = 0.28 mg/L). Reports on mammals have indicated that allyl alcohol requires activation by alcohol dehydrogenases (Adh) to form the highly reactive and toxic metabolite acrolein, which shows similar toxicity in zebrafish embryos and adults. To identify if a limited metabolic capacity of embryos indeed can explain the low allyl alcohol sensitivity of zebrafish embryos, we compared the mRNA expression levels of Adh isoenzymes (adh5, adh8a, adh8b and adhfe1) during embryo development to that in adult fish. The greatest difference between embryo and adult fish was found for adh8a and adh8b expression. Therefore, we hypothesized that these genes might be required for allyl alcohol activation. Microinjection of adh8a, but not adh8b mRNA led to a significant increase of allyl alcohol toxicity in embryos similar to levels reported for adults (LC50 = 0.42 mg/L in adh8a mRNA-injected embryos). Furthermore, GC/MS analysis of adh8a-injected embryos indicated a significant decline of internal allyl alcohol concentrations from 0.23-58 ng/embryo to levels below the limit of detection (< 4.6 µg/L). Injection of neither adh8b nor gfp mRNA had an impact on internal allyl alcohol levels supporting that the increased allyl alcohol toxicity was mediated by an increase in its metabolization. These results underline the necessity to critically consider metabolic activation in the zebrafish embryo. As demonstrated here, mRNA injection is one useful approach to study the role of candidate enzymes involved in metabolization.

EPA-0382 – Genetic alcohol sensitivity as an indicator of mental disorders

Objective To evaluate the association between genetic alcohol sensitivity ( ADH1B and ALDH2 polymorphisms) and mental disorders. Method A total of 1945 prefectural civil servants were screened and interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview. The mental disorders include major depressive disorder, dysthymia, suicidal risk, manic episode, panic disorder, agora phobia, social phobia, specific phobia, obsessive-compulsive disorder, general anxiety disorder, alcohol dependence/abuse, substance dependence/abuse, anorexia nervosa, anorexia bulimia, and PTSD. Genomic DNA was extracted from blood samples. TaqMan? SNP genotyping assays were used for the following (gene, SNP, assay ID): ADH1B , rs1229984, C_2688467_20; ALDH2 , rs671, C_11703892_10. Logistic regression analysis was used to evaluate those genetic polymorphisms and mental disorders adjusting for sex, age, and job rank. Results Alcohol sensitivity was genetically classified into five domains according to the combination of ADH1B and ALDH2 genotypes (type A, B, C, D and E). Preliminary analysis using 497 samples showed that low alcohol sensitivity (type A and B combined) was significantly associated with alcohol dependence/abuse (OR 2.71, 95% CI 1.44-5.10) compared to high sensitivity (type C, D, and E combined). Low alcohol sensitivity also showed non-significant modest association with any mental disorders except alcohol-related disorders (OR 1.99, 95% CI 0.72-5.48). Conclusions Low alcohol sensitivity might be associated with mental disorders, especially with alcohol-related disorders. Since the analysis has not been finished yet, the complete results will be shown in the congress.

Low Sensitivity to Alcohol: Relations With Hangover Occurrence and Susceptibility in an Ecological Momentary Assessment Investigation

The current investigation tested whether low sensitivity to alcohol, as measured by the Self-Rating of the Effects of Alcohol (SRE) form, is associated with hangover occurrence or resistance, two potentially important predictors of later problematic drinking outcomes. Drinkers who reported using alcohol at least four times in the past month (N = 402) completed the SRE at baseline and used ecological momentary assessment methods with an electronic diary to record drinking behaviors and related experiences over 21 days. Each morning, the diary assessed prior-night drinking behaviors and the presence of current hangover. After adjustments for sex, body weight, age, and smoking status, higher SRE scores (indicating lower alcohol sensitivity) predicted hangover occurrence on postdrinking mornings (odds ratio [OR] = 1.24 per interquartile range [IQR], p = .003). However, when the number of drinks consumed in the drinking episode was covaried, SRE scores were negatively associated with hangover (OR = 0.67 per IQR, p <.001). An interaction between SRE scores and the number of drinks consumed indicated that low-sensitivity drinkers tend to be differentially resistant to hangover at a given number of drinks. Higher SRE scores were associated with consuming more drinks on average (generalized estimating equations coefficient = 2.20 per IQR, p <.001). Individuals lower in alcohol sensitivity appear to be more resistant to hangovers per unit of alcohol. However, they are also more likely to engage in excessive drinking, and this may account for their increased odds of experiencing hangover during an arbitrary monitoring period. Heavy consumption, hangover resistance, and hangover frequency may each be manifestations of low sensitivity to alcohol, an established risk factor for alcohol use disorder.

Specificity of P3 event-related potential reactivity to alcohol cues in individuals low in alcohol sensitivity.

Recent research using event-related potentials (ERPs) has shown that individuals low in alcohol sensitivity show increased P3 reactivity to alcohol cues (Bartholow, Henry, & Lust, 2007). The current research sought to test the specificity of this effect by including other arousing cues in addition to alcohol, and by controlling for individual differences in trait impulsivity. Forty-seven participants varying in self-reported alcohol sensitivity completed a visual oddball task including neutral, arousing (erotic and adventure-related), and beverage-related images while ERPs were recorded. Low-sensitivity participants showed increased P3 reactivity to alcohol cues relative to their high-sensitivity peers. However, P3 amplitude elicited by all other targets did not differ as a function of alcohol sensitivity levels. Differences in impulsivity and recent alcohol consumption did not account for sensitivity group differences in alcohol cue reactivity. These results point to the specific motivational salience of alcohol cues to individuals at risk for alcohol problems because of low alcohol sensitivity and suggest that P3 reactivity to alcohol cues could be a new endophenotype for alcohol use disorder risk.

Associations ofALDH2andADH1BGenotypes With Alcohol‐Related Phenotypes in Asian Young Adults

Associations of ALDH2 and ADH1B genotypes with alcohol use have been evaluated largely using case-control studies, which typically focus on adult samples and dichotomous diagnostic outcomes. Relatively fewer studies have evaluated ALDH2 and ADH1B in relation to continuous drinking outcomes or at different developmental stages. This study examined additive and interactive effects of ALDH2 and ADH1B genotypes on drinking behavior in a mixed-gender sample of Asian young adults, focusing on continuous phenotypes (e.g., heavy episodic and hazardous drinking, alcohol sensitivity, drinking consequences) whose expression is expected to precede the onset of alcohol use disorders. The sample included 182 Chinese- and Korean-American young adults ages 18 years and older (mean age = 20 years). Effects of ALDH2, ADH1B and ethnicity were estimated using generalized linear modeling. The ALDH2*2 allele predicted lower reported rates of alcohol use and drinking consequences as well as greater reported sensitivity to alcohol. There were significant ethnic group differences in drinking outcomes, such that Korean ethnicity predicted higher drinking rates and lower alcohol sensitivity. ADH1B status was not significantly related to drinking outcomes. Ethnicity and ALDH2 status, but not ADH1B status, consistently explained significant variance in alcohol consumption in this relatively young sample. Results extend previous work by showing an association of ALDH2 genotype with drinking consequences. Findings are discussed in the context of possible developmental and population differences in the influence of ALDH2 and ADH1B variations on alcohol-related phenotypes.

Phorbol Ester Differentiates the Levels of [3H]MK-801 Binding in Rats Lines Selected for Differential Sensitivity to the Hypnotic Effects of Ethanol

These studies addressed the possible involvement between sensitivity to the hypnotic action of ethanol and function of the NMDA receptor. The studies were carried out using high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats, two rats having differential sensitivity to the acute hypnotic action of ethanol. The animal models were developed by a selective breeding experiment. Using a quantitative autoradiograph technique, it was demonstrated that [3H]MK-801 binding to the NMDA receptor was highest in hippocampus in both HAS and LAS rats, but significant [3H]MK-801 binding was also detected in cortex, caudate-putamen, and thalamus of HAS and LAS rats. The density of [3H]MK-801 binding was lower only in cerebellar granule layers of untreated HAS rats as compared to the same brain area in untreated LAS rats. Activation of protein kinase C (PKC) by 100 nM PDBu, increased [3H]MK-801 binding in cortex, caudate-putamen, thalamus, central gray, and cerebellum of HAS rats but activation of PKC did not influence [3H]MK-801 binding in LAS rats. These activation of PKC differentiates between [3H]MK-801 binding of HAS and LAS rats in frontal cortex (layer II-IV and cingulate), caudate-putamen, and ventral lateral thalamic nuclei. The basal level of PKC-gamma mRNA was higher in HAS rats than that of LAS rats. These results suggest that the activation of PKC potentiates NMDA receptor function of the rat line which is more sensitive to alcohol (HAS) but does not affect [3H]MK-801 binding of alcohol resistant (LAS) rats.

Quantitative Trait Loci Mapping for Ethanol Sensitivity and Neurotensin Receptor Density in an F2 Intercross Derived From Inbred High and Low Alcohol Sensitivity Selectively Bred Rat Lines

Genetic variance in initial sensitivity to ethanol has been implicated as a risk factor for the development of alcoholism. Identification of the genes that confer differential initial sensitivity is an important goal for the development of new treatment strategies and for a comprehensive understanding of the mechanism of ethanol's action. Quantitative trait loci (QTL) mapping for initial sensitivity and other ethanol-related behavioral traits in model organisms has become an important first step for the ultimate identification of genes that contribute to variation in ethanol responses. An F(2) intercross was made from the Inbred High and Low Alcohol Sensitivity rat lines (IHAS and ILAS). The F(2) rats were tested for duration of the loss of righting reflex test (LORR); blood ethanol concentration at regain of righting reflex (BECrrr); BEC at the first time to reach criterion on the rotarod after 1.6 g/kg of ethanol (BEC1); acute functional tolerance on the rotarod (AFT); and high-affinity neurotensin receptor (NTR1) density in the nucleus accumbens (NAc), caudate putamen (CP), and ventral midbrain (VMB). A full genome scan with an average marker spacing of 16.8 cM for interval QTL mapping was conducted on the F(2) rats (N = 363). Seven significant or suggestive QTL were detected for LORR, one for BECrrr, three for BEC1, two for NTR1 binding in the CP, and one for binding in the NAc, but none were mapped for AFT or NTR1 binding density in the VMB. Effect size of the seven LORR QTL, the trait for which the parental strains were selected, ranged from 3 to 4%, with all accounting for approximately 22% of the total phenotypic variation. One of the LORR QTL on chromosome 2 (approximately 87 cM) was significant, and a second QTL on chromosome 5 (approximately 37 cM) was suggestive for both LORR and BECrrr. The results indicate that segregating populations derived from the IHAS and ILAS strains can be used for mapping ethanol sensitivity QTL. The chromosome 2 LORR QTL may confer variation in ethanol metabolism, whereas the chromosome 5 LORR/BECrrr QTL likely mediates central nervous system ethanol sensitivity. The small number or absence of QTL for BEC1, AFT, and NTR1 receptor density suggests that genetic variation for these traits is minimal in the IHAS/ILAS strains and/or the effect size of QTL for these traits is too small to be mapped efficiently in this sample of F(2) rats. The ultimate identification of genes underlying these alcohol sensitivity QTL will contribute to our understanding of the actions of alcohol in the central nervous system if not to a deeper understanding of the genetic risk factors for alcoholism.

Differences in norepinephrine clearance in cerebellar slices from low-alcohol-sensitive and high-alcohol-sensitive rats

High-alcohol-sensitive (HAS) and low-alcohol-sensitive (LAS) rats were bred for sensitivity and insensitivity, respectively, to the sedative/hypnotic effects of ethanol. These rats also display differential sensitivity to the depressant effects of locally applied ethanol on cerebellar Purkinje neurons in vivo. We have found that LAS animals exhibit a greater influence of endogenous β–adrenergic activity on neuronal responses to γ-aminobutyric acid (GABA) and ethanol than do HAS animals. In the current study, we investigated the possibility that the regulation of synaptic norepinephrine levels by norepinephrine transporters could contribute to a differential β–adrenergic influence on GABA and ethanol sensitivity between HAS and LAS rats. We locally applied norepinephrine from a glass micropipette into the various layers of cerebellar brain slices prepared from LAS and HAS rats, and recorded the levels of norepinephrine clearance by using Nafion-coated carbon-fiber microelectrodes. Norepinephrine clearance was significantly faster by ∼64% in the Purkinje cell layer of HAS rats. No differences in norepinephrine clearance were found in the molecular or the granule layer between LAS and HAS rats. The catecholamine uptake inhibitor nomifensine reduced norepinephrine clearance in both rat lines. These findings support the hypothesis that regulation of synaptic norepinephrine levels by norepinephrine transporter activity in the Purkinje cell layer may contribute to the differential sensitivity of Purkinje neurons to ethanol and GABA in LAS and HAS rats.

Differential vulnerability to motor deficits in second replicate HAS and LAS rats following neonatal alcohol exposure

Children exposed prenatally to alcohol suffer from a variety of behavioral alterations. However, variation exists in the pattern and severity of these alcohol-related neurodevelopmental disorders. We examined the influence of alcohol sensitivity in the etiology of fetal alcohol effects by studying rat lines selectively bred for extremes in alcohol-induced sleep time: high-alcohol-sensitive (HAS) and low-alcohol-sensitive (LAS) rats. Using subjects from the first replicate, we previously reported that HAS rats exposed to alcohol during development were more vulnerable to ethanol-induced hyperactivity and motor deficits compared to LAS rats. To determine if these effects were, in fact, related to the trait for which these subjects were selected, the present study examined the consequences of developmental alcohol exposure in second replicate HAS and LAS rats. Second replicate HAS and LAS rats, as well as Sprague–Dawley rats, were exposed to 6.0 g/kg/day ethanol on Postnatal Days (PD) 4–9, a period of brain development equivalent to the third trimester, via an artificial rearing procedure. Artificially and normally reared controls were included. Activity was measured on PD 18–21 and parallel bar motor coordination on PD 30–32. Ethanol exposure produced hyperactivity in all genetic groups, and there were no differences among HAS and LAS rats. In contrast, consistent with findings from the first replicate, ethanol-exposed HAS rats were more impaired on the motor coordination task compared with LAS rats. These data suggest that genetically mediated responses to alcohol may relate to behavioral vulnerability to motor deficits following developmental alcohol exposure. They also provide evidence that genetic factors play a role in fetal alcohol effects and suggest that phenotypic markers may indicate individuals at high risk for some fetal alcohol effects.