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CORK Bibliography: Biological Markers of Substance Use

79 citations. January 2003 to present

Prepared: March 2009

Agrawal A; Pergadia ML; Balasubramanian S; Saccone SF; Hinrichs AL; Saccone NL et al. Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerstrom Test for Nicotine Dependence. Addiction 104(3): 471-477, 2009. (21 refs.)

A previous association analysis identified polymorphisms in gamma-aminobutyric acid receptor A, subunit 4 (GABRA4) and GABRA2 to be associated with nicotine dependence, as assessed by a score of 4 or more on the Fagerstrom Test for Nicotine Dependence (FTND). In the present report, we extend the previous study by expanding our genotyping efforts significantly for these two genes. In 1049 cases (FTND of 4 or more) and 872 controls (smokers with FTND of 0) from the United States and Australia, we examine the association between 23 GABRA4 and 39 GABRA2 recently genotyped single nucleotide polymorphisms (SNPs) and nicotine dependence using logistic regression-based association analyses using the genomic analysis package PLINK. Two and 18 additional SNPs in GABRA4 and GABRA2, respectively, were associated with nicotine dependence. The SNPs identified in GABRA4 (P-value = 0.002) were restricted to introns 1 and 2, exon 1 and the 5' end of the gene, while those in GABRA2 localized to the 3' end of the gene and spanned introns 9-3, and were in moderate to high linkage disequilibrium (as measured by r(2)) with each other and with previously studied polymorphisms. Our findings demonstrate consistently the role of GABRA4 and GABRA2 in nicotine dependence. However, further research is needed to identify the biological influence of these intronic variations and to isolate functionally relevant polymorphisms neighboring them.

Al-Delaimy WK; Stampfer MJ; Manson JE; Willett WC. Toenail nicotine levels as predictors of coronary heart disease among women. American Journal of Epidemiology 167(11): 1342-1348, 2008. (32 refs.)

The authors assess the ability of toenail nicotine levels as a biomarker to predict incident coronary heart disease (CHD). A nested case-control study was carried out among 62,641 women aged 36-61 years in the Nurses' Health Study cohort who provided toenail clippings in 1982. Between 1984 and 1998, 905 incident CHD cases were diagnosed and matched with two controls by age and date of toenail collection. Using multivariate logistic regression analyses, the authors found a statistically significant dose-response association between increasing toenail nicotine levels and risk of CHD (p(trend) < 0.0001); women in the highest quintile had a relative risk of 3.44 (95% confidence interval (CI): 2.56, 4.62) compared with women in the lowest quintile. With each increase in the log-transformed unit of continuous toenail nicotine levels, there was a 42% increase in the risk of CHD (relative risk = 1.42, 95% CI: 1.33, 1.52). The association remained significant when the number of cigarettes smoked and passive smoking were included as covariates (relative risk = 1.12, 95% CI: 1.01, 1.24). In conclusion, toenail nicotine levels are predictive of CHD among women independent of other risk factors and remained significant even after adjustment for history of cigarette smoking.

Al-Delaimy WK; Willett WC. Measurement of tobacco smoke exposure: Comparison of toenail nicotine biomarkers and self-reports. Cancer Epidemiology, Biomarkers & Prevention 17(5): 1255-1261, 2008. (31 refs.)

Background: Accurate measurement tools of exposure for use in large epidemiologic studies are lacking. Biomarkers of tobacco exposure provide additional advantages to self-reports and there is a need to further develop and validate them. The objective is to compare toenail nicotine levels, a novel biomarker of tobacco exposure, with self-reports of tobacco exposure from a large cohort study. Methods: In this cross-sectional analysis, toenail samples were collected from 2,485 women participating in the Nurses' Health Study in 1982. Detailed self-reports of smoking habits and reported exposure to second-hand smoke (SHS) were collected from these women near the time of toenail collection. The toenail samples were analyzed by a high-performance liquid chromatography method for measuring nicotine. Results: The 5 to 95 percentile range of toenail nicotine was from 0.06 to 4.06 ng/mg toenail and the median level was 0.21 ng/mg. There was a significant difference in toenail nicotine levels according to reported smoking status (the median level for nonsmokers with no SHS was 0.10 ng/mg, the median level for nonsmokers with SHS was 0.14 ng/mg, and the median level for active smokers was 1.77 ng/mg). However there was considerable overlap in nicotine levels according to reported smoking status. Toenail nicotine level was strongly associated with reported smoking level (Spearman r=0.63), but there was no complete concordance, suggesting that the two methods are measuring different aspects of the same exposure. Conclusion: Our findings show that toenail nicotine levels capture the overall burden of tobacco smoke exposure and provide additional information on exposure not captured by reported history.

Alling C; Chick JD; Anton R; Mayfield RD; Salaspuro M; Helander A et al. Revealing alcohol abuse: To ask or to test? Alcoholism: Clinical and Experimental Research 29(7): 1257-1263, 2005. (46 refs.)

This article represents the proceedings of a symposium at the 2004 ISBRA Congress in Heidelberg/Mannheim, Germany. The chairs were C. Alling and R. A. Harris. The presentations were (1) Advantage and Disadvantage of Tests for Self-Reported Intake in Different Settings, by J. D. Chick; (2) Update on the Use of Biological Markers to Monitor Outcome in Alcoholism Clinical Treatment Trials, by R. Anton; (3) Identification of Alcohol Biomarkers Using Genomic and Proteomic Approaches, by R. D. Mayfield; (4) Use of Biomarkers as Secondary or Primary Outcome Measures in Alcoholism Treatment Trials, by M. Salaspuro; and (5) Use of Tests for Drink-Drive Offenders: A European Perspective, by A. Helander.

Anton RF; Oroszi G; O'Malley S; Couper D; Swift R; Pettinati H et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence. Archives of General Psychiatry 65(2): 135-144, 2008. (64 refs.)

Context: Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response. Objective: To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. Design: Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. Setting: Eleven academic sites in the COMBINE Study. Participants: Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. Interventions: Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). Main Outcome Measures: Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. Results: Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P=. 07) and a decreased percentage of heavy drinking days (P=. 04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P=. 005). No gene X medication interactions were observed in those treated with both MM and CBI. Conclusions: These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 geno-typing in alcoholic individuals might be useful to assist in selecting treatment options. Trial Registration: clinicaltrials. gov Identifier: NCT00006206.

Anton RF; Youngblood M. Factors affecting %CDT status at entry into a multisite clinical treatment trial: Experience from the COMBINE study. Alcoholism: Clinical and Experimental Research 30(11): 1878-1883, 2006. (27 refs.)

Background: Carbohydrate-deficient transferrin (CDT) occurs as a higher percentage of normal transferrin (%CDT) in heavy drinkers. %CDT is used as a marker of both alcohol use disorder severity and treatment outcome both clinically and in treatment trials. Nevertheless, little is known about the parameters that predict which patients are %CDT positives at treatment entry. These parameters might include level of drinking, days of abstinence before testing, and severity of alcohol dependence before evaluation. Methods: %CDT levels were collected before randomization from participants of the COMBINE Study, a large federally sponsored multisite clinical trial evaluating medications and behavioral therapies in alcohol-dependent outpatients. %CDT (assayed in a central laboratory) was available in 1,193 individuals for whom drinking history in the 30 days before testing and measures of alcoholism severity were documented. The effects of drinking history and alcohol severity were evaluated for prediction of a %CDT-positive test status. Results: Less percent days abstinent (PDA) and more drinks per drinking day (DDD) were predictive of higher rates of %CDT-positive patients (maximum 67%). Up to 14 days of continuous abstinence before testing did not appear to significantly affect %CDT status. Rates of %CDT positives remained reasonably steady up to about 40% percent days abstinent. Years of drinking at dependence levels had an unexpected negative impact on %CDT-positive rates while previous treatment had a small but positive impact of %CDT-positive rates. ADS and DrInC scores had no predictive value over and above recent drinking amounts on %CDT status. Conclusions: %CDT is more likely to be positive in those who have more days of drinking and to a lesser degree in those who drink more per drinking day. It can remain positive even in those alcoholic subjects who stop drinking many days before testing. Alcoholic subjects with more treatment experiences appear to have a marginally higher %CDT-positive rate.

Appenzeller BMR; Schuman M; Yegles M; Wennig R. Ethyl glucuronide concentration in hair is not influenced by pigmentation. Alcohol and Alcoholism 42(4): 326-327, 2007. (16 refs.)

This work shows that the concentration of ethyl glucuronide (EtG) in hair, a marker for the evaluation of the alcohol consumption, is not influenced by the presence or absence of melanin. The results confirm that, unlike many other substances, the EtG determination in hair has not to take into account the hair colour for the correct interpretation of hair testing results.

Arfsten DP; Silbergeld EK; Loffredo CA. Fetal ADH23, maternal alcohol consumption, and fetal growth. International Journal of Toxicology* 23(1): 47-54, 2004. (47 refs.)

There is some evidence suggesting the allele for alcohol dehydrogenase 2*3 (ADH2*3) is associated with a protective effect against alcohol-related intrauterine growth retardation (IUGR). This study was conducted to explore the affect of the ADH2*3 allele on fetal growth. Bloodspots (n = 1016) belonging to individual infants of a subgroup of the Baltimore-Washington Infant Study (BWIS) were assayed for the presence of the ADH2*3 allele by a polymerase chain reaction (PCR)-based method. Infants genotyped for ADH2*3 were those for whom bloodspots were identified and obtained from the Maryland Newborn Screening Program. The effect of ADH2*3 and maternal alcohol consumption on intrauterine growth was explored by multivariable linear regression analysis. Twenty-six percent of the 306 blood spots belonging to African-American infants were positive for ADH2*3 (4% were homozygous and 22% were heterozygous). Only a small percentage of bloodspots for Caucasian (1.3%) were positive for the ADH2*3 allele. Consequently, further analysis concentrated on gene-exposure interactions for African-American infants. It was found that the incidence of being small-for-gestation-age (SGA) was lower for ADH2*3-positive infants (2.5% versus 8.8%; p =.08). SGA infants had elevated odds for being ADH2*3 negative (OR: 3.15, 95% C.I.: 0.70-14.26) and for being born to mothers that consumed alcohol during pregnancy (OR: 2.31, 95% C.I.: 0.77-6.91). A negative trend between maternal alcohol consumption and mean offspring birthweight was found; however, ADH2*3 did not have a significant impact on mean birthweight for infants born to mothers that drank during pregnancy. These results could be interpreted as possible support for the hypothesis that ADH2 genotype in the infant may impact risk for alcohol-related IUGR. However, this study has limitations in that it is a "nested study of convenience" and involves a relatively small number of infants born to mothers reporting moderate to heavy alcohol use during pregnancy.

Bar-Oz B; Klein J; Karaskov T; Koren G. Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse. Archives of Disease in Childhood 88(2): F98-F100, 2003. (88 refs.)

Background: Meconium and hair are two biological markers of in utero exposure to illicit drugs. Objective: To compare the sensitivity of the two tests for different drugs. Setting: Motherisk laboratory which tests in utero drug exposure in Toronto. Methods: Cocaine, benzoylecgonine, opiates, cannabis, benzodiazepines, methadone, and barbiturates were measured in pairs of hair and meconium samples from the same neonates. Results: Meconium was marginally more sensitive than neonatal hair for detection of cocaine and cannabis, possibly because it may detect second trimester exposure whereas hair grows only during the third trimester of pregnancy. There was a significant correlation between hair and meconium concentrations of cocaine, cannabis, and opiates. Conclusion: In cases of clinical suspicion and a negative neonatal urine test, both meconium and hair are effective biological markers of in utero illicit drug exposure. Meconium may be more sensitive, but neonatal hair is available for three months whereas meconium is available for only one or two days. In contrast, the use of meconium, being a discarded material, is more acceptable to some parents than hair testing, which entails cutting scalp hair from the newborn.

Bartholow BD; Henry EA; Lust SA. Effects of alcohol sensitivity on P3 event-related potential reactivity to alcohol cues. Psychology of Addictive Behaviors 21(4): 555-563, 2007. (56 refs.)

Although alcoholics and individuals at risk for alcoholism often show smaller amplitude of the P3 event-related brain potential (ERP), recent data (K. Namkoong, E. Lee, C. H. Lee, B. O. Lee, & S. K. An, 2004) indicate that alcohol-related cues elicit larger P3 amplitude in alcoholics than in controls. Little is known concerning the ERP profiles or alcohol cue reactivity of social drinkers at risk for alcoholism due to low sensitivity to alcohol's effects. Participants differing in alcohol sensitivity viewed images of alcoholic and nonalcoholic beverages while ERPs were, recorded and provided information about their alcohol use patterns at baseline and 4 months later. Compared to high-sensitivity participants, those low in sensitivity showed larger P3s to alcohol cues, even when recent alcohol use was statistically controlled for. Moreover, the P3 elicited by alcohol cues predicted alcohol use at follow-up, a finding supporting the idea that P3 amplitude reflects the motivational significance of substance-related cues. These findings point to risk status, not consumption history, as an important predictor of cue reactivity effects.

Bartholow BD; Pearson M; Sher KJ; Wieman LC; Fabiani M; Gratton G. Effects of alcohol consumption and alcohol susceptibility on cognition: A psychophysiological examination. Biological Psychology 64(1/2): 167-190, 2003. (59 refs.)

The present study sought to examine acute effects of alcohol on cognitive processing and performance within the context of two prominent theories of alcohol's effects; namely, that alcohol restricts the focus of attention (e.g. Steele and Josephs, 1990. Journal of Abnormal Psychology, 97, 196-205) and that alcohol impairs response inhibition (e.g. Fillmore and Vogel-Sprott, 1999. Experimental and Clinical Psychopharmacology, 7, 49-55; Fillmore and Vogel-Sprott, 2000. Journal of Studies on Alcohol, 61, 239-246). Forty-five participants were randomly assigned to receive either a placebo level of alcohol (0.04 g/kg), a moderate dose (0.40 g/kg), or a higher dose (0.80 g/kg). Brain electrical activity (ERPs) and behavioral responses (reaction time and accuracy) were measured while participants performed a modified flanker task, in which a target letter was flanked by response-compatible or response-incompatible letters. Analyses of behavioral data showed that alcohol increased response competition in accuracy but not response times, suggesting that alcohol influences response selection more than attentional processes per se. This finding is in-line with predictions derived from the response inhibition model. ERP latency data provided mixed support for both models. ERP amplitude data showed that the high dose of alcohol primarily influenced a mostly frontal negativity in the ERP, present on both correct and incorrect response trials. Differences in self-reported susceptibility to alcohol were most evident in the amplitude of the P3 component. Findings are discussed in terms of the differential effects of acute dose and susceptibility on information processing.

Bataille V; Ruidavets JB; Arveiler D; Amouyel P; Ducimetiere P; Perret B; Ferrieres J. Joint use of clinical parameters, biological markers and CAGE questionnaire for the identification of heavy drinkers in a large population-based sample. Alcohol and Alcoholism 38(2): 121-127, 2003. (38 refs.)

Aims: Alcohol consumption in France is one of the highest in the world. Factors associated with excessive alcohol drinking are numerous. However, taken separately, none of the existing clinical or biological markers of excessive alcohol intake enables an adequate identification of heavy drinkers. The aim of this cross-sectional survey was to identify socio-demographic, clinical and biological factors associated with excessive alcohol drinking, to develop a model and to assess its reliability, thus enabling the detection of heavy drinkers. Methods: Subjects were 1619 men and 1559 women, aged 35-64 years, living in three French areas (Lille, Strasbourg and Toulouse) and randomly selected from polling lists. Socio-demographic status, lifestyle, reported alcohol intake and answers to the CAGE questionnaire (alcohol dependence) were obtained by questionnaire. A blood sample was taken for quantification of biological parameters. Men who drank 60 g of ethanol a day (g/day) or above and women who drank 30 g/day or above were classified as heavy drinkers. The reference class (RC) gathered non-drinkers and moderate drinkers together. The sample was divided into two sub-samples: the first was used to estimate the parameters of a logistic regression model (heavy drinkers vs others), and the second to assess the accuracy of this model for the identification of heavy drinkers, using receiver operating characteristic (ROC) curves. A specific analysis was performed for each gender. Results: Fourteen per cent of men and 40.8% of women were non-drinkers. Nine per cent of women and 14.4% of men were heavy drinkers. Wine was the most consumed alcoholic beverage. In the univariate analyses, differences were observed between the two groups of alcohol consumers for most of the socio-demographic, clinical and biological variables considered. In the multivariate analyses, low educational level, smoking, apoprotein B, high density lipoprotein cholesterol, mean corpuscular volume (MCV), gamma-glutamyl-transferase (GGT) and the CAGE score for men, and living area, age, MCV, GGT and the CAGE score for women remained independently and significantly associated with heavy drinking. In the validation sub-sample, these models combining different types of markers enabled a good discrimination between heavy drinkers and the RC, with an area under the ROC curve of 82% for men and of 79% for women. Conclusions: In this study, socio-demographic, clinical and biological factors and the CAGE score were independently related to excessive alcohol drinking and their joint utilization in a screening model enabled a good recognition of heavy drinkers.

Bearer CF. Meconium as a biological marker of prenatal exposure. Ambulatory Pediatrics 3(1): 40-43, 2003. (33 refs.)

Pediatricians often come in contact with patients with neurodevelopmental problems. Demonstrating the cause of the dysfunction is extremely difficult. Implicated etiologic factors include prenatal exposure to a wide variety of chemical agents, including alcohol, tobacco, pesticides, and heavy metals. The ubiquitous nature of these agents in the environment indicates a need to develop a method to ascertain the extent of exposure. A unique and novel approach to this problem is to analyze biological samples (matrices) that accumulate in utero, such as hair, for these chemicals and/or their metabolites. Meconium may be such a matrix. Initial work on meconium, starting in 1989, showed its utility in identifying drug-exposed infants. Current research is aimed at 1) broadening the list of chemical agents that can be detected in meconium; 2) determining the relationship between maternal exposure assessed from either blood/urine samples or questionnaire data and the quantity of chemical/metabolite in the meconium (eg, X mg/mL of cotinine in meconium signifies Y number of cigarettes smoked per day by the mother); and 3) determining the significance of the amount of chemical/metabolite in the meconium (eg, X mg/mL of ethanol metabolites identifies an infant who will have significant behavior problems in school). Few data currently describe these important relationships. In the future, clinicians may be able to submit a sample of meconium for analysis to determine the nature and extent of a child's exposure in utero to a wide variety of drugs and chemicals and to predict the impact of the exposure on the child. This article summarizes work on developing and validating meconium as an indicator of prenatal exposure.

Belfer I; Hipp H; McKnight C; Evans C; Buzas B; Bollettino A et al. Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Molecular Psychiatry 11(3): 301-311, 2006. (44 refs.)

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P = 0.001) and Plains Indian (P = 0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (X and < mean HA of population). In the Finns, haplotype (P < 0.0001) and diplotype (P < 0.0001) distributions differed between high HA alcoholics, low HA alcoholics and nonalcoholics. Our results from two independent populations suggest that GAL may contribute to vulnerability to alcoholism, perhaps mediated by dimensional anxiety.

Benegal V; Antony G; Venkatasubramanian G; Jayakumar PN. Gray matter volume abnormalities and externalizing symptoms in subjects at high risk for alcohol dependence. Addiction Biology 12(1): 122-132, 2007. (61 refs.)

Reduced right amygdala volumes have been reported in young, alcohol-naive subjects at high risk (HR) for alcohol dependence. The differences in brain morphometry have been associated with an excess of externalizing behaviors in these subjects. This may reflect a neurobiological vulnerability to alcohol dependence. Existing Magnetic Resonance Imaging (MRI) studies on these subjects have examined only a few, pre-selected brain regions using the manual regions of interest (ROI) approach. MRI of HR subjects (n = 20) and age, sex, and handedness-matched low-risk (LR) subjects (n = 21) were analyzed using optimized voxel-based morphometry and ROI approach. The externalizing symptoms of these subjects and their fathers were measured using the Semi-Structured Assessment for the Genetics of Alcoholism. HR subjects had significantly smaller volumes of superior frontal, cingulate and parahippocampal gyri, amygdala, thalamus and cerebellum. These gray matter volumes correlated negatively with externalizing symptoms scores. Subjects at HR for alcoholism have reduced volumes of critical areas of brain gray matter, which are associated with increased externalizing symptoms. These represent key endophenotypes of alcoholism.

Brunelle C; Assaad J-M; Pihl RO; Tremblay RE; Vitaro F. Brief report: Exaggerated ethanol-induced cardiac reactivity as an indicator of increased risk for gambling. Psychology of Addictive Behaviors 17(1): 83-86, 2003. (30 refs.)

Pathological gambling and alcohol dependence show a high rate of co-occurrence. Some individuals at risk for alcohol dependence display an exaggerated heart rate (HR) increase following alcohol consumption, a characteristic suggesting sensitivity to reward. This study examined whether exaggerated ethanol-induced cardiac reactivity was associated with increased gambling behaviors. One hundred five young men (M = 20.13 years, SD = 1.07) consumed 1 ml of ethanol (95% volume) per kilogram of body weight. HR was measured and participants completed the South Oaks Gambling Screen (SOGS; H. R. Lesieur & S. B. Blume, 1987). Those with higher intoxicated HRs reported significantly greater scores on the SOGS (p = .02). This suggests that ethanol-induced HR increase is a possible marker for addictive disorders.

Cannon DS; Baker TB; Piper ME; Scholand MB; Lawrence DL; Drayna DT et al. Associations between phenylthiocarbamide gene polymorphisms and cigarette smoking. Nicotine & Tobacco Research 7(6): 853-858, 2005. (16 refs.)

Phenotypic evidence indicates that the ability to taste the bitter compounds phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) may protect against cigarette smoking. In this study, PTC gene haplotypes were found to be associated with both the odds of being a smoker and the importance of cigarette taste as a smoking motive. Smokers (n = 384) and nonsmokers (n = 183) were genotyped for polymorphisms that affect taste sensitivity to PTC and PROP. The "taster" PAV haplotype, relative to the "nontaster" AVI haplotype, was predicted to be associated with reduced odds of being a smoker and lower taste motivation as measured by the Wisconsin Inventory of Smoking Dependence Motives-68 taste/sensory processes scale. The results did not support the predicted association between the PAV and AVI haplotypes and smoker odds, but the AAV haplotype, which confers intermediate PTC/PROP taste sensitivity, was associated with reduced smoker prevalence (49% vs. 700/o), X-2(1, N= 567) = 10.392, p=.001. The predicted relationship between PAV and AVI and taste motivation was found, F(2, 348)=3.303, p=.038. The results encourage further exploration of the role of taste/sensory processes in tobacco dependence.

Chen CC; Yin SJ. Alcohol abuse and related factors in Asia. International Review of Psychiatry 20(5): 425-433, 2008. (78 refs.)

Alcohol problems are a global issue, and the nature of alcohol abuse is very complicated. The susceptibility to alcohol abuse varies greatly from one individual to another and also from one nation to another, depending on the availability of alcohol, a country's regulation related to alcohol, a country's cultural background, religious tradition and its economics. Alcohol dependence is also a complicated disease process. The prevalence of alcohol dependence also varies greatly from one ethnic group to another. Asia is the world's largest and most populous continent. The natural disasters, religious conflicts as well as political disputes cause people lack of opportunity in many countries. People in this region do not consume more alcohol than the people in the rest of the world. The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socio-economic factors, but also biological factors influence drinking behaviour. Findings of functional genetic polymorphism of the major alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) have led to the suggestion that this enzyme system may possibly play a diverse but critical role in alcohol dependence and in the alcohol-related disease process in the different ethnic groups. This paper reviews alcohol problems and related factors. Their management and prevention strategy are discussed.

Chen L; Wang MY; Villalta PW; Luo XH; Feuer R; Jensen J et al. Quantitation of an acetaldehyde adduct in human leukocyte DNA and the effect of smoking cessation. Chemical Research in Toxicology 20(1): 108-113, 2007. (17 refs.)

Acetaldehyde is one of the most prevalent carcinogens in cigarette smoke. It is also a major metabolite of ethanol and is found widely in the human diet and environment. Acetaldehyde DNA adducts are critical for its carcinogenic properties. The role of acetaldehyde DNA adducts in human cancer related to tobacco and alcohol exposure could be investigated with a suitable biomarker. Therefore, in this study, we have developed a method for analysis of the major DNA adduct of acetaldehyde, N-2-ethylidene-dGuo (1), in human leukocyte DNA. Leukocyte DNA was subjected to enzyme hydrolysis in the presence of NaBH3CN, which converts adduct 1 to N-2-ethyl-dGuo (2). [N-15(5)]N-2-ethyl-dGuo was used as the internal standard. After solid-phase extraction, N-2-ethyl-dGuo was quantified by LC-ESI-MS/MS-SRM. The method was sensitive, accurate, and precise, and applicable to low microgram amounts of DNA. It was applied to investigate the effect of smoking cessation on levels of adduct 1, measured as adduct 2. Twenty-five smokers who were only light drinkers were eligible for the study. Levels of adduct 2 were quantified at two baseline time points separated by one week and again after four weeks of abstinence from smoking and alcohol consumption. The mean (+/- S.D.) levels of adduct 2 measured in the leukocytes of the smokers were 1310 +/- 1720 (range 124-7700) and 1120 +/- 1140 (range 138-5760) fmol/mu mol dGuo at the two baseline points and 705 +/- 438 (range 111-1530) fmol/mu mol dGuo after 4 weeks of cessation. The median level of adduct 2 decreased significantly by 28% upon quitting smoking (P = 0.02). These results demonstrate that the major acetaldehyde DNA adduct can be reliably quantified by MS/MS methods in human leukocyte DNA and that cigarette smoking has a modest but significant effect on its levels.

Chen YJ; Chen C; Wu DC; Lee CH; Wu CI; Lee JM et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisins on esophageal cancer risks. International Journal of Cancer 119(12): 2827-2831, 2006. (32 refs.)

In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer. A multicenter hospital-based case-control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1-4). Polymorphisms of ADH1B and ALDH2 were genotyped by the method of PCR-RFLP. Individuals with ADH1B*1/*1 genotype had a 3.99-fold risk (95% CI = 2.13-7.48) of developing esophageal cancer, compared with those with ADH1B*2/*2 genotype, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99-fold risk (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, of developing esophageal cancer, compared with those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes of ADH1B and ALDH2 on esophageal cancer risk. These results suggest that ADH1B and ALDH2 polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.

Couture S; Brown TG; Ouimet MC; Gianoulakis C; Tremblay J; Carbonneau R. Hypothalamic-pituitary-adrenal axis response to stress in male DUI recidivists. Accident Analysis and Prevention 40(1): 246-253, 2008. (64 refs.)

Cortisol is a stress hormone mediated by the hypothalamic-pituitary-adrenal (HPA) axis and a psychobiological marker of genetic risk for alcoholism and other high-risk behavioural characteristics. In previous work with driving under the influence of alcohol (DUI) recidivists, we uncovered a significant inverse relationship between the frequency of past DUI convictions and salivary cortisol, whose strength surpassed those observed between DUI frequency and measures of alcohol abuse and other DUI-related characteristics. This finding emerged using a methodology not specifically contrived to test this relationship. The goals of this follow-up study were to (a) examine if a standardized stress-induction protocol would produce a significant inverse relationship between cortisol response and number of DUI offences; and (b) clarify whether HPA axis dysregulation could be linked to particular DUI-related behavioural correlates, such as alcohol use severity, sensation seeking, and antisocial features. Thirty male DUI recidivists were recruited as well as I I male non-DUI drivers as a comparison group. Results indicated an inverse relationship between DUI frequency and cortisol response (r(39) = -0.36, p = 0.021), as well as a lower cortisol response in DUI offenders than the comparison group (F(1,39) = 5.71, p = 0.022). Finally, for recidivists, hierarchical regression analyses indicated that experience seeking (R-2 = 0.23, p = 0.008), followed by number of cigarettes smoked daily (R-Delta(2) = 0.12, p = 0.031), combined to explain 35% of the variance in cortisol (F(2,29) = 7.26, p = 0.003). These findings indicate that severe recidivism may have psychobiological underpinnings, and that HPA axis dysregulation appears to be a mechanism common to high-risk behaviours including DUI recidivism, sensation seeking, and cigarette smoking.

Duranceaux NCE; Schuckit MA; Luczak SE; Eng MY; Carr LG; Wall TL. Ethnic differences in level of response to alcohol between Chinese Americans and Korean Americans. Journal of Studies on Alcohol and Drugs 69(2): 227-234, 2008. (47 refs.)

Objective: Koreans have higher rates of alcohol-use disorders and family history of alcoholism, compared with Chinese. These differences likely reflect both environmental and genetic influences. One genetically influenced characteristic that may contribute to these ethnic differences is level of response to alcohol. Variant alleles of aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH1B) genes are prevalent in individuals of Asian heritage and have been associated with an increased level of response to alcohol and a decreased risk for alcohol dependence. Additionally, a low level of response to alcohol is more common in individuals with a first-degree family history of alcoholism and is predictive of increased risk for this disorder. It also is possible that sociocultural factors have an impact on an individual's response to alcohol. The current study examined self-report level of response to alcohol, ALDH2 and ADH1B, country of origin, and family history of alcoholism in 154 Chinese- and 181 Korean-American college students. Method: Participants were evaluated via in-person interviews and genotyped at the ALDH2 and ADH1B loci. Results: Ethnicity was significantly related to level of response to alcohol, with Koreans having a lower self-reported level of response than Chinese. This relationship remained significant after considering the effects of gender, height, weight, quantity and frequency of alcohol consumption (over the previous 90 days), ALDH2 genotype, ADH1B genotype, country of origin, and first-degree family history of alcohol dependence. Conclusions: The results suggest that a low level of response to alcohol may contribute to the increased risk for alcohol abuse and dependence found in Koreans, relative to Chinese. More research is needed to determine additional factors that may be contributing to the low alcohol response and high rates of alcoholism in Koreans.

Ehlers CL; Phillips E. EEG low-voltage alpha and alpha power in African American young adults: Relation to family history of alcoholism. Alcoholism: Clinical and Experimental Research 27(5): 765-772, 2003. (56 refs.)

Background: Several studies support an association between having a low-voltage EEG and alcohol dependence; however, it is not clear whether this measure represents a risk marker or is a result of years of heavy drinking. The present study's aims were to investigate the prevalence of low-voltage alpha EEG variants in African American young adults who have not yet developed alcohol dependence and to test for associations between low-voltage alpha (LVA) EEG, alpha power, and a family history of alcohol dependence. Methods: Clinical ratings and spectral characteristics of the EEG, collected using bipolar recordings, were investigated in 81 African American young adult men and women (18-25 years old) who had no personal history of alcohol dependence. Information on psychiatric diagnoses, personality features, personal drinking and drug use history, and family history (FH) of alcoholism was obtained. Results: Thirty-two percent (n=26) of the participants had an LVA EEG variant, and an additional 22% (n=18) had borderline LVA. The presence of an LVA variant was not associated with drinking status, a family history of alcoholism, or a personal history of anxiety disorders but was associated with significantly higher extroversion scores. Participants who had an FH of alcoholism had significantly higher spectral power in the slow alpha frequencies (7.5-9 Hz). FH was not associated with any significant differences in any other EEG frequency band. Conclusions: These findings suggest that considerable ethic variation may exist in the prevalence of LVA EEG variants. In addition, like findings in other populations of non-African descent, having an FH of alcohol dependence may be associated with significantly higher voltage in the alpha frequency ranges.

Ehlers CL; Phillips E; Sweeny A; Slawecki CJ. Event-related potential responses to alcohol-related stimuli in African-American young adults: Relation to family history of alcoholism and drug usage. Alcohol and Alcoholism 38(4): 332-338, 2003. (70 refs.)

Aims: To use event-related potentials (ERPs) to investigate the response to alcohol-related stimuli in African-American young adults. Methods: ERPs to an object recognition task, that included pictures of objects, food and alcohol-related and non-alcohol-related drinks as stimuli, were obtained in 81 African-American young adult men and women (18-25 years old) without a personal history of alcohol dependence. Information on: psychiatric diagnoses, personal drinking and drug use history, and familial history of alcoholism was also obtained. Results: Family history was found to be associated with lowered P3 components and higher N1 components in response to the non-alcohol-related drinks. Additionally, an exploratory analyses revealed that lower amplitude N1 components were generated in response to alcohol-related stimuli in regular marijuana users compared with non-regular users. No associations of N1 or P3 amplitudes with conduct disorder symptoms or current drinking status were found in this population. Conclusions: These studies demonstrated that family history is significantly and selectively associated with lower P3 amplitudes in this group of young adult men and women of African-American heritage. Additionally, current usage of marijuana and alcohol do not modify P3 amplitudes. However, regular marijuana use may diminish N1 response to alcohol-related stimuli, whereas, family history of alcoholism may augment N1 responses. Taken together these studies further suggest that ERPs can provide specific information on alcoholism risk as well as use of other misused drugs.

Elkashef A; Vocci F. Biological markers of cocaine addiction: Implications for medications development. (review). Addiction Biology 8(2): 123-139, 2003. (69 refs.)

The search for effective medications for cocaine addiction has been elusive. The failure to find such medications so far could be due to poor understanding of the underlying biology both in the premorbid condition and following the disease state of chronic cocaine use. Population heterogeneity could be a major factor in response to medications. In an attempt to highlight the issue of biomarkers we reviewed physiological, neuroendocrine and neuroimaging studies to identify specific biological changes/markers that could be used to characterize subgroups among chronic cocaine users. Merging the biology within medications studies of cocaine abusers could prove useful for targeting specific pharmacological agents to subgroups of patients, prediction of response to medication and relapse to use.

Epstein RS. What's needed for personalized therapy in smoking cessation, (editorial). Clinical Pharmacology & Therapeutics 84(3): 309-310, 2008. (7 refs.)

it has long been known that smoking cessation is one of the most cost-effective public health opportunities available. The fact that some 22% of americans smoke, 1 despite overwhelming evidence of the consequences, reflects in part the addictive aspects of smoking and the generally modest effectiveness of various strategies for quitting. Although one of the US Department of Health and Human Services goals for the year 2010 is universal coverage of smoking-cessation agents, only about a third of payers currently cover the cost of such agents. A major disincentive is that the return on investment has been modeled to take at least 5 years to reach the break-even point, given the cost of the individual agents, the high recidivism rates, the timeline for influencing outcomes, and the relative ineffectiveness of studied agents in broad or untargeted populations. The article by Patterson et al. in this issue intriguingly suggests that there might be a way to use smokers' phenotypes to determine before treatment initiation which smokers will respond to which therapy. This approach could greatly improve the overall effectiveness of smoking-cessation agents and generate cost savings that might in turn have the effect of influencing more payers to cover these agents.

Fein G; Chang M. Visual P300s in long-term abstinent chronic alcoholics. Alcoholism: Clinical and Experimental Research 30(12): 2000-2007, 2006. (59 refs.)

Background: Evidence of reduced P3b amplitudes in chronic alcoholics and individuals at risk for developing alcoholism suggest that the P3b may be an endophenotypic marker for alcoholism. If this is the case, then long-term abstinent alcoholics (LTAAs) should exhibit reduced P3b amplitudes. Thus far, P3b studies on chronic alcoholics have focused primarily on samples with relatively short-term abstinence (less than 15 months). This study examines the amplitude and latency of the P3b and P3a event-related brain electrical components in LTAAs compared with normal controls (NCs) and whether these measures are related to alcohol use and other subject variables. Methods: Electroencephalographs (EEGs) were recorded on 48 LTAAs (mean abstinence=6.7 years) compared with 48 age-matched and gender-matched NCs during a visual P300 experiment consisting of standard, target, and rare nontarget conditions. This paradigm elicited the P3b (target condition) and the P3a (rare nontarget condition) components. Results: Long-term abstinent alcoholics had reduced P3b amplitudes and increased P3b latencies in comparison with NCs. Long-term abstinent alcoholics also exhibited delayed P3a components, but no P3a amplitude reductions. Alcohol use variables, a family history of alcohol problems, and the duration of alcohol abstinence were not associated with any amplitude or latency variables. Conclusions: Even after very prolonged abstinence, reduced P3b amplitudes are present in chronic alcoholics and are not associated with any family history or alcohol use variables. These results provide equivocal support for reduced P3b amplitude being an endophenotypic marker for alcoholism, but are also consistent with P3b being affected by a threshold of alcohol abuse, with the effect not resolving over long periods of abstinence.

Fein G; Whitlow B; Finn P. Mismatch negativity: No difference between controls and abstinent alcoholics. Alcoholism: Clinical and Experimental Research 28(1): 137-142, 2004. (35 refs.)

Background: A number of studies have examined the amplitude of the mismatch negativity (MMN) evoked potential as a measure of a brain inhibitory deficit in alcoholics or those at risk for alcoholism. The current study examined MMN in alcoholics abstinent an average of 6.7 years (with a minimum of six months abstinence) compared to controls. This study examined the association of MMN with alcoholism family history density, with indices of the presence and severity of externalizing disorders (a risk-factor for alcoholism), and with alcohol use variables. Methods: Electroencephalograms were gathered on 76 subjects (38 controls, 38 abstinent alcoholics) during a nonattending mismatch negativity experiment. Measures of alcoholism family history density, disinhibited personality traits, and antisocial symptoms served as measures of risk-factors known to be associated with a genetic liability to alcoholism. Alcohol use variables were used as measures of alcoholism severity. Results: There were no differences in MMN amplitude or latency between controls and abstinent alcoholics. There also were no significant associations between MMN measures and the measures of risk for alcoholism or with the severity of alcohol use or duration of abstinence. Conclusions: The results suggest that MMN is neither affected in chronic alcoholics nor associated with alcoholism vulnerability, and thus does not reflect a trait marker of alcoholism or alcoholism risk. The current results do not address effects on MMN of acute alcohol ingestion or withdrawal from alcohol.

Filbey FM; Claus E; Audette AR; Niculescu M; Banich MT; Tanabe J et al. Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry. Neuropsychopharmacology 33(6): 1391-1401, 2008. (68 refs.)

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems.

Florescu A; Ferrence R; Einarson T; Selby P; Soldin O; Koren G. Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: Focus on developmental toxicology. (review). Therapeutic Drug Monitoring 31(1): 14-30, 2009. (147 refs.)

Active and passive smoking have been associated with an array of adverse effects on health. The development of valid and accurate scales of measurement for exposures associated with health risks constitutes an active area of research. Tobacco smoke exposure still lacks an ideal method of measurement. A valid estimation of the risks associated with tobacco exposure depends on accurate measurement. However, some groups of people are more reluctant than others to disclose their smoking status and exposure to tobacco. This is particularly true for pregnant women and parents of young children, whose smoking is often regarded as socially unacceptable. For others, recall of tobacco exposure may also prove difficult. Because relying on self-report and the various biases it introduces may lead to inaccurate measures of nicotine exposure, more objective solutions have been suggested. Biomarkers constitute the most commonly used objective method of ascertaining nicotine exposure. Of those available, cotinine has gained supremacy as the biomarker of choice. Traditionally, cotinine has been measured in blood, saliva, and urine. Cotinine collection and analysis from these sources has posed some difficulties, which have motivated the search for a more consistent and reliable source of this biomarker. Hair analysis is a novel, noninvasive technique used to detect the presence of drugs and metabolites in the hair shaft. Because cotinine accumulates in hair during hair growth, it is a unique measure of long-term, cumulative exposure to tobacco smoke. Although hair analysis of cotinine holds great promise, a detailed evaluation of its potential as a biomarker of nicotine exposure, is needed. No studies have been published that address this issue. Because the levels of cotinine in the body are dependent on nicotine metabolism, which in turn is affected by factors such as age and pregnancy, the characterization of hair cotinine should be population specific. This review aims at defining the sensitivity, specificity, and clinical utilization of different methods used to estimate exposure to cigarette smoking and environmental tobacco smoke.

Fortuna JL; Smelson DA. The phenomenon of drug craving. Journal of Psychoactive Drugs 40(3): 255-261, 2008. (67 refs.)

The phenomenology of drug craving has become the focus of much research within addictive disorders because of the belief that desire plays a role in maintaining the addiction. Many of the studies have focused on the activation of neural pathways, particularly within the dopamine system in response to specific events or stimuli. While many of these studies have focused on a particular drug of choice, little has been done across addictive disorders. This article will present and review phenomena that induce drug craving, as well as delineate precise neural pathways which are activated during craving and specific neurobiological markers which are associated with an increased risk for drug craving and other forms of addictive behavior.

Friedrich N; Husemoen LLN; Petersmann A; Nauck M; Volzke H; Linneberg A. The association between alcohol consumption and biomarkers of alcohol exposure with total serum immunoglobulin E levels. Alcoholism: Clinical and Experimental Research 32(6): 983-990, 2008. (34 refs.)

Background: A number of studies have shown that self-reported alcohol intake is positively associated with total serum immunoglobin E (IgE) levels. The purpose of the present study was to investigate the association of self-reported alcohol consumption and different biomarkers of alcohol exposure to total serum IgE levels in a general adult population. Methods: A total of 3,443 subjects aged 20 to 79 years from the population-based cross-sectional Study of Health in Pomerania (SHIP) were included in the analyses. Information on alcohol consumption and serum carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), aspartate-amino transferase (ASAT), andalanine-amino transferase (ALAT) levels were measured. Multivariable linear regression models were performed separately in atopic and nonatopic subjects. Results: In nonatopic subjects positive associations between self-reported alcohol consumption as well as all considered biomarkers of alcohol exposure and total serum IgE levels were found. Further the results also suggested positive associations between alcohol consumption as well as alcohol biomarkers and total serum IgE level in atopic subjects, even though not all tests for linear trend reached statistical significance. Conclusions: In conclusion, biomarkers of alcohol exposure were positively associated with total serum IgE levels supporting that the positive association between self-reported alcohol intake and IgE levels observed in previous studies is real and not due to misclassification of alcohol intake or confounding by other factors that may be linked to both alcohol intake and total serum IgE levels.

Fromme K; de Wit H; Hutchison KE; Ray L; Corbin WR; Cook TAR et al. Biological and behavioral markers of alcohol sensitivity. Alcoholism: Clinical and Experimental Research 28(2): 247-256, 2004. (50 refs.)

This article summarizes a symposium that was organized by Dr. Kim Fromme and presented at the 2003 annual meeting of the Research Society on Alcoholism in Ft. Lauderdale, Florida. The four presentations illustrate the emerging technologies and methods that are now being used to investigate the genetic basis of differential sensitivity to alcohol and their behavioral manifestations. Combining human genotyping with laboratory measures of behavior and subjective reports, these presentations represent state-of-the-art approaches to crossing the bridge from the Decade of the Brain to the Decade of Behavior. Dr. De Wit's paper describes her research on the neurobiological basis for individual differences in sensitivity to the stimulant and sedative effects of alcohol. Evidence suggests that activity of the dopaminergic and GABAergic neurotransmitters underlie these stimulant and sedative effects, respectively. Both Drs. Hutchison's and Corbin's papers describe their research on polymorphisms for the serotonin transporter (SLC6A4) as a determinant of the subjective effects of alcohol challenge. Dr. Hutchinson's and Ms. Ray's findings indicate that individuals with the short form of the SLC6A4 alleles (S) demonstrated a low level of response to alcohol, thus supporting previous research that the S allele may be associated with increased risk for alcohol dependence. In contrast, Dr. Corbin did not find a reliable association between the SLC6A4 genotype and subjective response to alcohol. Mr. Cook's and Dr. Wall's paper adds another dimension to this article by presenting research on both the aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH2) genetic variants and their association with the alcohol-related flushing response that is prevalent in Asian populations. Dr. David Goldman provides concluding remarks.

Gamma A; Brandeis D; Brandeis R; Vollenweider FX. The P3 in 'ecstasy' polydrug users during response inhibition and execution. Journal of Psychopharmacology 19(5): 504-512, 2005. (52 refs.)

Substance abuse and associated externalizing disorders are characterized by behavioural disinhibition and low impulse control, with reduced neural inhibition postulated to be the common underlying brain mechanism. The P3 component of event-related potentials (ERPs) is a widely used neurophysiological measure thought to reflect inhibitory brain processes, but as yet has not been assessed in ecstasy users. We recorded ERPs evoked by a Continuous Performance Test (CPT) in 16 current ecstasy polydrug users and 17 controls. The CPT included conditions where a prepared motor response had to be executed (Go) or inhibited (NoGo). Both controls and ecstasy users showed normal, robust patterns of P3 anteriorization and delay in the NoGo compared to the Go condition. Ecstasy users had tower P3 amplitudes at midline electrodes and a less anterior Location of NoGo P3 peaks. These effects became weaker after statistically controlling for age, educational level and lifetime cannabis use. White Lower P3 amplitudes are consistent with higher levels of neural disinhibition in ecstasy polydrug users, the normal switch pattern between response execution and inhibition, and the less anterior location of the NoGo P3, do not indicate disturbed inhibitory brain mechanisms.

Graham AW; Schultz TK; Mayo-Smith MF; Ries RK; Wilford BB, eds. Principles of Addiction Medicine. Chevy Chase MD: American Society of Addiction Medicine, 2003. (Chapter refs.)

This volume is a comprehensive text on addictions. It is organized into 14 major sections, each of which has multiple chapters. There are over 200 contributors. The sections deal with the following themes: basic science and core concepts; pharmcology; diagnosis, assessment and early intervention; overview of addiction treatment; management of intoxication and withdrawal; pharmacologic interventions; behavioral interventions; 12-step programs and other recovery-oriented interventions; alcohol and drug problems in the workplace; medical disorders and complications of addiction; co-occurring addictive and psychiatric disorders; pain and addiction; and children and adolescents. There are also six appendices.

Gregg EO; Fisher AL; Lowe F; McEwan M; Massey ED. An approach to the validation of biomarkers of harm for use in a tobacco context. Regulatory Toxicology and Pharmacology 44(3): 262-267, 2006. (26 refs.)

There is both a call and a need for biomarkers of harm that are validated for use in a tobacco context. Currently, there are no validated biomarkers and there is no consensus about which ones may be suitable for this purpose. To advance the science in this area a working definition of biomarkers of harm and a shortlist of candidate biomarkers are proposed. A framework for the validation of biomarkers of harm using of a series of epidemiological studies culminating in a targeted prospective study is outlined. The candidate biomarkers have advanced to preliminary testing although this does not imply that any on the shortlist will become validated. This framework could also be used for the evaluation of proteomic, genomic, transcriptosomic or metabonomic profiles, which may turn out to be the preferred biomarkers for use in harm prediction. Biomarker studies would complement data that are generated from specific in vitro tests and from animal studies to evaluate tobacco products.

Habeych ME; Charles PJ; Sclabassi RJ; Kirisci L; Tarter RE. Direct and mediated associations between P300 amplitude in childhood and substance use disorders outcome in young adulthood. Biological Psychiatry 57(1): 76-82, 2005. (94 refs.)

Background: Attenuated amplitude of the P300 wave has been frequently documented in youths at high risk for substance use disorders (SUDs). This investigation bad two aims: 1) determine whether P300 amplitude in late childhood is a predictor of SUD outcome by age 19; and 2) evaluate whether neurobehavior disinhibition (ND) mediates this association. Methods: Boys (aged 10-12) were recruited through proband biological fathers with either a lifetime DSM-III-R diagnosis of SUD (N = 67) or no adult psychiatric disorder (N = 94). P300 amplitude was recorded during an auditory oddball task. Neurobehavior disinhibition was evaluated using tests of executive cognitive function, behavior undercontrol, and emotion dysregulation. The relationship is assessed using multiple and logistic regressions. Results: Substance use disorder by age 19 was significantly predicted by P300 amplitude (odds ratio [OR] = .958; 95% confidence interval [CI] = .918-.999; Wald chi(2) = 3.992; df = 1; p = .045) and ND score (OR = 1.060; 95% CI = 1.023-1.098; Wald chi(2) 10.267; df = 1; p = .0014) measured at age 10 to 12. P300 amplitude also significantly correlated with ND severity (beta = -.217; t = -2.412; df = 6,160; p = .017). Low P300 amplitudes were observed in children who succumbed to SUD by age 19. Conclusions: These results indicate that ND mediates the association between attenuated P300 amplitude in childhood and SUD at age 19; however, P300 amplitude is not a specific childhood marker of SUD.

Hansell NK; Pang D; Heath AC; Martin NG; Whitfield JB. Erythrocyte aldehyde dehydrogenase activity: Lack of association with alcohol use and dependence or alcohol reactions in Australian twins. Alcohol and Alcoholism 40(5): 343-348, 2005. (43 refs.)

Aim: Aldehyde dehydrogenase 1 (ALDH1) has been advocated as a marker of alcohol intake. The absence or low levels of ALDH1 may be associated with alcohol-induced flushing or other reactions to alcohol in Europeans and therefore, with reduced alcohol use. This study tested whether variation in erythrocyte ALDH1 activity was associated with alcohol use, alcohol dependence or reactions to alcohol in unselected subjects of European descent, and whether variation in ALDH1 activity was subject to genetic influences. Methods: ALDH activity was measured in erythrocytes from 677 men and women who had participated in a twin study of alcohol use and dependence. Results: There were no significant effects of sex, alcohol consumption or alcohol dependence on ALDH activity. Subjects who reported reactions to alcohol did not have low activity. Women aged below 45 years had lower ALDH activity than men or older women. The heritability of ALDH activity was 56% (95% confidence interval = 42-67%). Conclusions: Previous reports that erythrocyte ALDH activity is low in alcoholics were not substantiated in this community-based sample. Associations with alcohol reactions were not found. ALDH activity varies widely between subjects, largely because of genetic factors.

Hill SY; Muddasani S; Prasad K; Nutche J; Steinhauer SR; Scanlon J et al. Cerebellar volume in offspring from multiplex alcohol dependence families. Biological Psychiatry 61(1): 41-47, 2007. (58 refs.)

Background: Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the cerebellum in regulating cognitive functions is being increasingly recognized along with its well-known influence on motor performance. Additionally, developmental changes in cerebellar volume during adolescence have been reported. Methods: Magnetic resonance imaging was used to measure the cerebellum in 17 high-risk adolescent and young adult offspring from multiplex alcohol dependence families and 16 control subjects matched for gender, age, and IQ. Results: High-risk (HR) adolescents/young adults showed increased total cerebellum volume and total grey in comparison with control subjects. Age-related decreases in total grey volume were seen with age, a pattern that was not seen in HR offspring. Conclusions: Offspring from multiplex families for AD manifest genetic susceptibility by having larger cerebellar volume, which seems to be related to lesser grey matter pruning for age. Larger cerebellar volumes in adult obsessive compulsive disorder (OCD) patients have been reported. This suggests a possible similarity in structural underpinnings for alcohol dependence and OCD.

Ho AMC; Tang NLS; Cheung BKL; Stadlin A. Dopamine receptor D4 Gene-521C/T polymorphism is associated with opioid dependence through cold-pain responses. Annals of the the New York Academy of Sciences. Drug Addiction: Research Frontiers and and Treatment Advances 1139: 20-26, 2008. (39 refs.)

Heroin users exhibit abnormal pain sensitivity called opioid-induced hyperalgesia that may weaken their determination to abstain. The dopamine receptor D4 gene (DRD4) is associated with heroin dependence; one of its polymorphisms is a C/T variation 521 by upstream to the gene (-521C/T). We investigated whether this polymorphism was related to opioid dependence through modulation of cold-pain responses. We recruited 84 heroin-dependent Chinese male subjects and 168 healthy male Chinese controls. Genotyping was performed by PCR-RFLP A significantly higher T allele frequency was observed in the heroin group (P = 0.041). Of the cohort recruited, 43 current heroin users and 66 controls were further subjected to a cold-pressor test (CPT) to determine their pain threshold and tolerance. TT controls demonstrated a significantly lower pain threshold than did their CC/CT counterparts (P = 0.022) and TT opioid users (P = 0.006). Moreover, CC/CT controls had a significantly higher pain tolerance than TT controls (P = 0.042) and CC/CT opioid users (P = 0.010). The data suggest that DRD4 -521C/T plays an important role in opioid dependence through modulating cold-pain responses. TT individuals might have a higher tendency to use opioids because they experience pain less strongly after chronic opioid use.

Houston RJ; Bauer LO; Hesselbrock VA. Effects of borderline personality disorder features and a family history of alcohol or drug dependence on P300 in adolescents. International Journal of Psychophysiology 53(1): 57-70, 2004. (67 refs.)

Decrements in P300 amplitude have been associated with familial risk for alcoholism as well as several other psychiatric disorders characterized by disinhibited behavior. The present study examined the P300 in relation to Borderline Personality Disorder (BPD) features in adolescents with a paternal history of alcohol or drug dependence. One hundred and seventy-five males and females, aged 14-20, were assigned to groups based on BPD features (BPD+ vs. BPD-), family history of substance dependence (negative FH-, alcohol FHA, drug FHD) and gender. BPD features were assessed using the Structured Clinical Interview for the DSM-III-R questionnaire. P300 ERPs were recorded while each subject per-formed the Stroop color-word compatibility test. Repeated measures analyses, which included Conduct Disorder and Depression symptoms as covariates, indicated a significant reduction in P300 amplitude in the BPD+ group. There were no significant effects of FH or gender on P300 amplitude. These results document the presence of neurophysiological abnormalities associated with BPD features in an adolescent sample. This effect appeared to be independent of a family history of alcohol or substance dependence. These findings suggest that BPD symptoms during adolescence are relevant to the examination of the physiological antecedents of those forms of adult psychopathology characterized by behavioral disinhibition, including alcohol and drug dependence.

Husemoen LLN; Fenger M; Friedrich N; Tolstrup JS; Fredriksen SB; Linneberg A. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcoholism: Clinical and Experimental Research 32(11): 1984-1991, 2008. (59 refs.)

Background: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking. In a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. Methods: The study population consisted of 1,216 Danish men and women aged 15-77 years participating in a health examination in 1998. The health examination included a self-administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume (E-MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. Results: Self-reported alcohol drinking was significantly associated with increasing levels of ALAT, E-MCV, high-density lipoprotein cholesterol, and blood pressure. The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge-drinking, and the ALDH1b1 ala69val polymorphism was associated with diastolic blood pressure. We did not find any statistically significant interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. Conclusions: In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene-environment interactions. More large-scale epidemiologic studies are needed to confirm theses results and to further investigate genetic susceptibility to the effects of alcohol drinking.

Iacono WG; Malone SM; McGue M. Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude. International Journal of Psychophysiology 48(2): 147-178, 2003. (165 refs.)

We hypothesize the existence of an inherited predisposition for a spectrum of behaviors and traits characterized by behavioral disinhibition. This externalizing spectrum includes childhood disruptive disorders, antisocial behavior, substance use disorders, personality traits related to behavioral undercontrol, and the precocious expression of problem behavior. We further hypothesize that a genetically influenced central nervous system diathesis underlies this spectrum and is reflected in reduced P300 amplitude in a visual oddball event-related potential task. A review of evidence bearing on the model is derived from findings from the Minnesota Twin Family Study, a population-based, longitudinal investigation of twin youth. These findings indicate that the collection of attributes related to behavioral disinhibition is familial, heritable, and interrelated. Evidence supporting P3 amplitude reduction (P3-AR) as an index of genetic vulnerability for this externalizing spectrum includes its association with (a) familial risk for substance use and antisocial personality disorders, (b) diagnoses of childhood disruptive disorders and substance use disorders, (c) early onset of undersocialized behavior, and (d) quantitative phenotypes related to externalizing problems. In addition, the development of substance use disorders over a 3-year period is associated with P3-AR measured prior to their expression. These findings suggest that P3-AR indexes one aspect of the genetic diathesis for a spectrum of externalizing problem behavior.

Jacobson SW; Stanton ME; Molteno CD; Burden MJ; Fuller DS; Hoyme HE et al. Impaired eyeblink conditioning in children with fetal alcohol syndrome. Alcoholism: Clinical and Experimental Research 32(2): 365-372, 2008. (43 refs.)

Background: Eyeblink conditioning (EBC) is a Pavlovian paradigm that involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Animal studies have shown that binge consumption of alcohol during pregnancy impairs EBC and that this impairment is likely mediated by a loss of neurons in the inferior olive and the cerebellar cortex and deep nuclei, as well as by a reduction in neural plasticity in the cerebellar deep nuclei. Methods: Short delay EBC was examined in 98 5-year-old children born to women from the Coloured (mixed ancestry) community in Cape Town, South Africa, who were recruited prenatally and are participating in the first prospective longitudinal study of children with fetal alcohol syndrome (FAS). FAS status was assessed at 5 years by expert dysmorphologists. Two sessions of 50 trials each were administered to the children; a third session was administered the following day to those children who did not meet criterion of 40% conditioned responses in session 2. Results: Not a single child with FAS met criterion for conditioning as contrasted with 75.0% of the controls. Whereas 86.7% of the controls who were conditioned met criterion by the end of Session 2, a large proportion of the relatively few alcohol-exposed nonsyndromal children who conditioned did not do so until Session 3. These alcohol effects on EBC persisted after controlling for IQ. Three of 4 microcephalic children who were not exposed to alcohol were successfully conditioned. Conclusions: This is the first prospective study to demonstrate impaired EBC in children diagnosed with FAS. Successful EBC in a microcephalic group supports the inference that the EBC deficit is specific to prenatal alcohol exposure and a potential biomarker for diagnosis of exposed children lacking the distinctive FAS dysmorphology. Delay EBC has a high sensitivity for identifying individuals with a diagnosis of probable FAS.

Johnstone E; Benowitz N; Cargill A; Jacob R; Hinks L; Day I et al. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clinical Pharmacology & Therapeutics 80(4): 319-330, 2006. (39 refs.)

Background: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. Methods. We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. Results: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P =.02), plasma nicotine concentration (P < .0001), and age (P =.02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F1,492 = 4.05, P =.04). Conclusion: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Junghanns K; Tietz U; Dibbelt L; Kuether M; Jurth R; Ehrenthal D et al. Attenuated salivary cortisol secretion under cue exposure is associated with early relapse. Alcohol and Alcoholism 40(1): 80-85, 2005. (34 refs.)

Aims: To test whether the risk of relapse in alcohol dependence is predicted by the subjective experience of cue exposure (CE) and/or cortisol reactivity to alcohol cues. Methods: Salivary cortisol and self-ratings of 'tension' and 'desire to drink' were measured in 32 detoxified alcohol-dependent inpatients during CE sessions conducted in the first and third week of motivation enhancement therapy. Subjects completed the Toronto Alexithymia Scale (TAS-20) and the Abbreviated Alcohol Expectancy Questionnaire (B-AEQ) towards the end of the inpatient treatment to measure emotional self-awareness and the expected positive effects of alcohol. Results: Six weeks after the end of the inpatient treatment, 15 patients were abstinent. Relapse was verified or was presumed for 17 patients. Those who had relapsed had shown an attenuated response to CE in the third week as an inpatient but did not differ from abstainers in terms of subjective reaction to cues. Subjective ratings of CE were not related to salivary cortisol or relapse but showed several associations with factors one and two of the TAS-20. The expectancy of enhanced social contacts by using alcohol (factor 1 of the B-AEQ) correlated negatively with the decline in salivary cortisol during the CE session in the third week of treatment. Subjective ratings of CE correlated with Alexithymiascores. Conclusions: Alcoholic patients who use alcohol to enhance their social contacts typically lack hypothalamo-hypophyscal-pituitary-adrenocortical (HPA) reactivity in the early period of abstention. They are at an increased risk of early relapse and perhaps use alcohol to increase cortisol secretion again.

Kampov-Polevoy AB; Garbutt JC; Khalitov E. Family history of alcoholism and response to sweets. Alcoholism: Clinical and Experimental Research 27(11): 1743-1749, 2003. (68 refs.)

Background: The relationship between a hedonic response to sweet tastes and a propensity to excessive alcohol drinking is supported by both animal and human studies. This study was designed to test the hypothesis that the genetic risk for alcoholism as measured by a paternal history of alcoholism in young social drinkers is associated with sweet-liking, defined as rating the strongest offered sucrose solution (i.e., 0.83 M) as the most palatable during the standard sweet test. Methods: Participants were 163 subjects (39% male) without a lifetime history of alcohol or drug abuse or dependence. Eighty-one subjects had a paternal history of alcoholism (FH+), and 82 did not (FH-). Each subject rated a series of sucrose solutions for intensity of sweetness and palatability. Subjects were categorized as sweet-likers if they rated the highest sucrose concentration as the most pleasurable. Results: The estimated odds of being a sweet-liker were 2.5 times higher for FH+ than for FH- subjects. FH+ subjects disliked the tastes of the two weakest offered sucrose concentrations (0.05 and 0.10 M), whereas FH- subjects reported these tastes to be neutral. Conclusions: The results of this study support the hypothesis that sweet-liking is associated with a genetic vulnerability to alcoholism.

Kampov-Polevoy AB; Ziedonis D; Steinberg ML; Pinsky I; Krejci J; Eick C/. Association between sweet preference and paternal history of alcoholism in psychiatric and substance abuse patients. Alcoholism: Clinical and Experimental Research 27(12): 1929-1936, 2003. (68 refs.)

Background: The relationship between preference for stronger sweet solutions and propensity to excessive alcohol drinking is supported by both animal and human studies. This study was designed to test the hypothesis that sweet preference is associated with the genetic risk of alcoholism as measured by a paternal history of alcoholism. Methods: Participants were 180 patients admitted to a residential treatment program for the treatment of alcoholism, drug dependence, or psychiatric conditions. In addition to a routine medical examination, patients completed the standard sweet preference test twice (on the 9th and 24th days after admission), and the family history of alcoholism was evaluated. Results: Sweet preference was shown to be stable over time. It was strongly associated with a paternal history of alcoholism, with family history-positive patients approximately 5 times more likely to prefer stronger sweet solutions than family history-negative subjects. Such factors as dependence on alcohol, cocaine, opiates, cannabis, other drugs (including prescription drugs), and tobacco smoking, as well as demographics (gender and age), did not significantly interfere with association between sweet preference and paternal history of alcoholism. Conclusions: These findings provide some support for the hypothesis that preference for stronger sweet solutions is associated with a genetic predisposition to alcoholism as measured by a paternal history of alcoholism.

Kapusta ND; Plener PL; Schmid R; Thau K; Walter H; Lesch OM. Multiple substance use among young males. Pharmacology, Biochemistry and Behavior 86(2): 306-311, 2007. (45 refs.)

Neurobiological studies hypothesize a common final pathway of addictive behavior in the mesolimbic dopaminergic system. Nicotine has been shown to sensitize the reward pathway, thereby causing increased drug-seeking behavior. Since there is evidence to suggest that nicotine, alcohol and other psychoactive substances act on the same final pathway and seem to augment their effects in animal subjects, drug intake behavior of humans would likely be reflected in increased substance use of nicotine-dependent persons. We used biological markers of substance use as well as questionnaires to assess the levels of psychoactive substance use among 18-year-old males in a naturalistic cross-sectional setting. We found that increasing levels of nicotine dependence were related to higher levels of alcohol abuse and dependence. Furthermore, higher levels of nicotine dependence were associated with elevated levels of recent cannabinoid use.

Karahalil B; Coskun E; Emerce E. ADRA2A polymorphism and smoking in a Turkish population. Toxicology and Industrial Health 24(3): 171-176, 2008. (20 refs.)

Adrenoceptors (ARs) consist of nine subtypes, which are involved in a wide spectrum of physiological functions and are the site of action for a considerable percentage of currently prescribed therapeutics. All AR subtypes (except alpha(1D)) can be polymorphic because of the genetic variations in the coding and non-coding regions. Sixteen sequence variations were identified in a-adrenergic 2A (ADRA2A) gene. Among them. ADRA2A C1291G polymorphism is one of the most important polymorphisms. which plays a major role in regulating neurotransmitter release, blood pressure, lipolysis. insulin secretion, and platelet aggregation. A C-G transversion results in an Mspl restriction frament length polymorphism located at 1291 bp upstream of the origin of transcription. Because Medline search showed no study showing the allelic frequencies, and no information is available on inter-individual variability of ADRA2A C1291G polymorphism in Turkish Population, we genotyped 203 healthy Turkish subjects. Because of large genetic variation of the polymorphism, we aimed to find out the distribution of C1291G polymorphism in Turkish population. Furthermore. we evaluated the possible association between the C1291G polymorphism in the ADRA2A receptor gene and smoking. The frequencies For the 1291C and 1291G alleles were 64%, and 36%, respectively. The genotype frequencies for C1291, C1291G, and G1291G were 35.5%, 57.6%, and 6.9%, respectively, in Turkish population. The allelic frequencies (1291C and 1291G) and G1291G homozygous variant genotype were similar to those reported in different Caucasian populations; however, C1291C and C1291G genotypes were different. We also observed that the frequency of the G allele was slightly higher in smoker subjects and lower among controls. The A DRA2A G allele may play a role in the predisposition to smoking. There is a need for expanding genotype and haplotype studies because of its importance in various physiological disorders and to confirm the association of this polymorphism with smoking.

Keskinoglu P; Cimrin D; Aksakoglu G. Relationships between cotinine, lower respiratory tract infection, and eosinophil cationic protein in children. European Journal of Pediatrics 166(5): 455-459, 2007. (26 refs.)

Introduction: The aim of this study was to investigate the effect of passive smoking on urine eosinophil cationic protein (u-ECP) in children with lower respiratory tract infections (LRTI). Method: This was a case-control study. The study cohort consisted of 150 children with LRTI (case group) and 150 healthy children (control), all from a urban setting. The statistical parameters were: a minimum of 139 children for a 95% confidence interval (95% CI), 80% power, and a possible exposure prevalence of 50%. The u-cotinine and u-ECP levels were measured by radioimmunoassay and fluoroimmunoassay methods, respectively. Data were analyzed by the McNemar chi-square test, t-test, and Pearson correlation. Results: When the generally accepted cut-off level of 30 ng/mg urinary cotinine/creatinine was applied, 87.3% of the children with LRTI and 84.7% of healthy children were passive smokers. Using a cut-off level of 60 ng/mg, passive smoking increased the prevalence of LRTI by 4.7-fold (p=0.000). The mean u-ECP values were significantly higher in the case group than in the healthy control group (p=0.018). A positive association was found between u-cotinine and u-ECP values in children with LRTI (p=0.034). Conclusion: The results of this study indicate that passive smoking may play an important role in the development of respiratory infections and can cause airway inflammation in children with existing LRTI.

Koob GF. The neurobiology of addiction: A neuroadaptational view relevant for diagnosis. Addiction 101(Supplement 1): 23-30, 2006. (51 refs.)

Aims: The purpose of this review is to provide a synthesis of our knowledge of the neurobiological bases of addiction relevant for the diagnosis of addiction. Methods: A heuristic framework of neuroadaptive changes within key brain neurocircuitry responsible for different stages of the addiction cycle is outlined and linked to human studies to provide important future translational links for diagnosis. Results: Animal studies have revealed dysregulation of specific neurochemical mechanisms (dopamine, opioid peptides) in the brain reward systems and recruitment of brain stress systems (corticotropin-releasing factor) during the development of dependence that convey vulnerability to relapse. Animal studies have implicated the prefrontal cortex and basolateral amygdala in drug- and cue-induced relapse, respectively, and the brain stress systems in stress-induced relapse. Genetic studies suggest roles for the genes encoding the neurochemical elements involved in both the brain reward and stress systems in the vulnerability to addiction, and molecular studies have identified transduction and transcription factors that may mediate dependence-induced reward dysregulation. Human imaging studies reveal similar neurocircuits involved in acute intoxication, chronic drug dependence and vulnerability to relapse. Conclusions: Major neurobiological changes in substance abuse disorders common to human and animal studies relevant for diagnosis include a compromised reward system, overactivated brain stress systems and compromised orbitofrontal/prefrontal cortex function. No biological markers of substance abuse disorders currently exist, but there are many promising neurobiological features of substance abuse disorders that will eventually aid in the specific diagnoses of substance use, misuse and dependence.

Lappalainen J; Kranzler HR; Petrakis I; Somberg LK; Page G; Krystal JH et al. Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus. Molecular Psychiatry 9(3): 312-319, 2004. (29 refs.)

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains >30000000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125-126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P=0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P=0.01), D1S2804 (126.16 cM, P=0.04), and D1S2776 (126.16 cM, P=0.02), which are all located within a <350000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

McClure JB. Motivating prepartum smoking cessation: A consideration of biomarker feedback. (review). Nicotine & Tobacco Research 6(Supplement 2): S153-S161, 2004. (49 refs.)

Maternal smoking is the single most important modifiable cause of poor pregnancy outcomes in the United States. To further reduce prepartum smoking prevalence, new and innovative treatment strategies have been called for. According to the Public Health Service's clinical practice guideline, one counseling strategy that warrants further investigation is use of biomarker feedback to educate women about the adverse effects of their smoking and the risks it poses to their health and the health of their unborn children. Many women who fail to quit smoking during pregnancy underestimate its risks. Providing tangible evidence of smoking-related risk may help motivate future cessation attempts. This article looks at the rationale and evidence for using biomarker feedback as a cessation aid during pregnancy. Limitations of the existing research and key considerations for future investigations are presented.

Meyerhoff DJ; Durazzo TC. Proton magnetic resonance spectroscopy in alcohol use disorders: A potential new endophenotype? (review). Alcoholism: Clinical and Experimental Research 32(7): 1146-1158, 2008. (140 refs.)

Background: Current effort is directed at defining new classification schemes for alcohol use disorders (AUD) based on genetic/biological, physiological, and behavioral endophenotypes. Methods: We describe briefly findings of in vivo brain proton magnetic resonance spectroscopy (H-1 MRS) studies in AUD and propose that they be further explored and expanded regarding their value as a potential endophenotype for AUD. Results: In vivo H-1 MRS, as part of the emerging field of "imaging genomics," may provide readily accessible, objective, functionally significant and region-specific neurobiological measures that successfully link genotypes to neurocognition and to psychiatric symptomatology in relatively small patient cohorts. We discuss several functional gene variants that may affect specific H-1 MRS-detectable metabolites and provide recent data from our own work that supports the view of genetic effects on metabolite measures. Conclusions: MRS-genetics research will not only offer clues to the functional significance and downstream effects of genetic differences in AUD, but, via monitoring and/or predicting the efficacy of pharmacological and behavioral interventions as a function of genotype, has the potential to influence future clinical management of AUD.

Mulert C; Juckel G; Giegling I; Pogarell O; Leicht G; Karch S et al. A Ser9Gly polymorphism in the dopamine D3 receptor gene (DRD3) and event-related P300 potentials. Neuropsychopharmacology 31(6): 1335-1344, 2006. (73 refs.)

An important reason for the interest in P300 event-related potentials are findings in patients with psychiatric disorders like schizophrenia or alcoholism in which attenuations of the P300 amplitude are common findings. The P300 wave has been suggested to be a promising endophenotype for genetic research since attenuations of the amplitude and latency can be observed not only in patients but also in relatives. In parallel, the search for genes involved in the pathogenesis of psychiatric disorders has revealed for both, schizophrenia and alcoholism an association with a DRD3 Ser9Gly polymorphism in a number of studies. In the present study, we have investigated 124 unrelated healthy subjects of German descent and have found diminished parietal and increased frontal P300 amplitudes in Gly9 homozygotes in comparison to Ser9 carriers. This finding suggests a possible role of the DRD3 receptor gene in the interindividual variation of P300 amplitudes. Further studies should address the direct role of the DRD3 Ser9Gly polymorphism in attenuated P300 amplitudes in psychiatric disorders like schizophrenia or alcoholism.

Murillo R; Crucilla C; Schmittner J; Hotchkiss E; Pickworth WB. Pupillometry in the detection of concomitant drug use in opioid-maintained patients. Methods and Findings in Experimental Clinical Pharmacology 26(4): 271-275, 2004. (19 refs.)

Pupillometry and ocular response measures are sensitive to a variety of acutely administered drugs and as such are useful for drug detection and fitness-for-duty applications. The utility of pupillometry to complement urine testing in methadone clinics, where there is considerable non-therapeutic drug use, has not been tested. A video-based pupillometer (FIT 2000) was evaluated in 37 opioid-maintained patients. Three times a week they provided urine samples and pupillometry measures of initial diameter (ID) in mm; constriction amplitude (CA) in mm; constriction latency (CL) in msec; and saccadic velocity (SV) in min/sec. Analysis of the success rates indicated that 92.9% (if subjects obtained an acceptable reading, 59% on the first attempt. Low variability in pupillarly parameters on drug-free days are necessary for effective identification of concomitant drug use. The variability (standard deviation) of ID (0.51 vs. 0.68), CA (0.12 vs. 0.27) and SV (7.2 vs. 11.1) increased on days when the urine was positive for abused drugs compared with drug-free urine days in subjects (n = 6). Subjects who were always drug-free (it = 4) had lower variability than those who always had urine positive for additional drugs (n = 20). These preliminary results suggest that pupillometry may be useful to verify concomitant drug use in a methadone-maintained population. Successful implementation of the methodology could reduce costly and intrusive urine testing.

Ostrea EM; Hernandez JD; Bielawski DM; Kan JM; Leonardo GM; Abela MB et al. Fatty acid ethyl esters in meconium: Are they biomarkers of fetal alcohol exposure and effect? Alcoholism: Clinical and Experimental Research 30(7): 1152-1159, 2006. (58 refs.)

Background: Biomarkers of fetal exposure to alcohol are important to establish so that early detection and intervention can be made on these infants to prevent undesirable outcomes. The aim of this study was to analyze long-chain fatty acid ethyl esters (FAEEs) in meconium as potential biomarkers of fetal alcohol exposure and effect. Methods: Fatty acid ethyl esters were analyzed in the meconium of 124 singleton infants by positive chemical ionization gas chromatography/mass spectrometry (GC/MS) and correlated to maternal ethanol use. Results: A total of 124 mother/infant dyads were enrolled in the study: 31 were in the control group and 93 were in the alcohol-exposed group. The incidence (28% vs 9.7%, p=0.037) of ethyl linoleate detected in meconium was significantly higher in the alcohol-exposed groups than the control groups. Similarly, when the concentrations of ethyl linoleate in meconium were grouped (trichotomized), there was a significant linear by linear association between alcohol exposure and group concentrations of ethyl linoleate (p=0.013). Furthermore, only alcohol-exposed infants were found in the group with the highest ethyl linoleate concentration. The sensitivity of ethyl linoleate in detecting prenatal alcohol exposure was only 26.9%, and its specificity and positive predictive value were 96.8 and 96.2%, respectively. There was no significant correlation between the concentration of ethyl linoleate in meconium and absolute alcohol consumed (oz) per drinking day across pregnancy, although a trend toward a positive correlation is seen at lower amounts of alcohol consumed. Among the polyunsaturated, long-chain FAEEs, there was weak evidence that the incidence (21.5% vs 6.5%, p=0.057) and concentration (p=0.064) of ethyl arachidonate (AA) were significantly higher in the alcohol-exposed groups than the control groups. Ethyl linolenate and ethyl docosahexanoate (DHA) in meconium were found only in the alcohol group, although not at statistically significant levels. Highly significant correlations were found among the concentrations of ethyl linoleate, ethyl linolenate, ethyl AA, and ethyl DHA in meconium (correlations ranged between r(s)=0.203, p=0.024; and r(s)=0.594, p < 0.001). Conclusion: We conclude that FAEEs in meconium, particularly ethyl linoleate and ethyl AA, are biomarkers of high specificity for prenatal exposure to alcohol in newborn infants. We also propose that ethyl AA and DHA could be potential biomarkers of fetal alcohol effects on the developing fetal brain and should be investigated further.

Otani K; Ujike H; Sakai A; Okahisa Y; Kotaka T; Inada T et al. Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence. Neuroscience Letters 434(1): 88-92, 2008. (43 refs.)

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p = 0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p = 0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.

Patterson F; Schnoll RA; Wileyto EP; Pinto A; Epstein LH; Shields PG et al. Toward personalized therapy for smoking cessation: A randomized placebo-controlled trial of bupropion. Clinical Pharmacology and Therapeutics 84(3): 320-325, 2008. (32 refs.)

We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3'-hydroxycotinine/cotinine derived during smoking, before entering a placebo-controlled randomized trial of bupropion plus counseling. At the end of the 10-week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6-month follow-up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation.

Pinto E; Reggers J; Gorwood P; Boni C; Scantamburlo G; Pitchot W et al. The short allele of the serotonin transporter promoter polymorphism influences relapse in alcohol dependence. Alcohol and Alcoholism 43(4): 398-400, 2008. (24 refs.)

Aims: The short (S) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR) contributes to the risk of alcohol dependence and co-occurring clinical features. We studied the putative link between this allele and relapse. Methods: 48 alcohol-dependent male patients were recruited and genotyped for the 5-HTTLPR. Relapse to alcohol drinking was monitored during 3 months after standardized withdrawal. Results: The S allele was significantly associated with relapse (p = 0.008) while no other factor that was measured played a significant role. Conclusions: The S allele of the 5-HTTLPR polymorphism may influence the risk of relapse in abstinent alcohol-dependent patients, possibly through intermediate phenotypes.

Politi L; Morini L; Leone F; Polettini A. Ethyl glucuronide in hair: Is it a reliable marker of chronic high levels of alcohol consumption? Addiction 101(10): 1408-1412, 2006. (14 refs.)

Aims: This study aims to investigate the relationship between ethanol daily intake (EDI) and the levels of ethyl glucuronide in hair. Design: Ethyl glucuronide concentration was determined in hair samples from different classes of ethanol drinkers and results were compared with the reported information about drinking habits. Setting Pavia, Italy. Participants: Twenty-two known alcoholics, 21 volunteers self-reporting an EDI from 2 to 60 g, and seven teetotallers were involved in this study. Measurements Ethyl glucuronide determination in hair samples was performed by liquid chromatography-tandem mass spectrometry (limit of detection: 2 pg/mg, lower limit of quantification: 3 pg/mg). Findings Current known alcoholics (n = 21) had ethyl glucuronide hair concentration in the range 4.0 - 434.7 pg/mg (average: 62.8, median 37.4 pg/mg); ethyl glucuronide was not detected in hair samples from teetotallers (n = 7); all volunteers reporting an EDI of at least 30 g (non-moderate drinkers' according to the US Department of Health and Human Services) tested positive for ethyl glucuronide (cut-off: 4 pg/mg). All volunteers declaring an ethanol daily intake higher than 40 g (`heavy drinkers' according to the World Health Organization, Regional Committee for Europe) tested positive for this compound (cut-off: 5 pg/mg). The application of a cut-off of either 4 pg/mg or 5 pg/mg resulted in one false positive, coming from a volunteer asserting an ethanol daily intake of 30 g. No false negatives were found. Conclusions: The concentration of ethyl glucuronide in hair appears to correlate with EDI.

Pombo S; Levy P; Bicho M; Ismail F; Cardoso JMN. Neuropsychological function and platelet monoamine oxidase activity levels in type I alcoholic patients. Alcohol and Alcoholism 43(4): 423-430, 2008. (93 refs.)

Aims: To explore neuropsychological function in two differentiated patterns of platelet monoamine oxidase B (MAO B) activity in alcoholic patients. Methods: Neuropsychological examination and platelet MAO B activity extracted from blood were collected from 42 alcohol-dependent patients recruited in the alcoholism unit (NETER) of the Psychiatric Service of Santa Maria University Hospital. Results: Alcoholics presented significantly low levels of platelet MAO B activity, when compared with control subjects; platelet MAO B activity in alcoholics classified as "under average subgroup" showed significant lower scores in the Raven Progressive Matrix and higher scores in hostility dimension, when compared with platelet MAO B activity in "above average subgroup." Conclusions: Results suggested platelet MAO B as a trait marker also to type I alcohol-dependent patients and the two observed associations between platelet MAO B activity with neurocognitive measures of executive functions (nonverbal reasoning) and psychopathological dimension such as hostility may support the notion about the effect of platelet MAO B activity in the further development of an impulsive cognitive style.

Proia NK; Paszkiewicz GM; Nasca MAS; Franke GE; Pauly JL. Smoking and smokeless tobacco-associated human buccal cell mutations and their association with oral cancer: A review (review). Cancer Epidemiology, Biomarkers & Prevention 15(6): 1061-1077, 2006. (135 refs.)

Reported herein are the results of a structured literature review that was undertaken to (a) determine if human buccal (mouth) cell changes are associated with smoking and smokeless ("chewing") tobacco, (b) tabulate different buccal cell alterations that have been reported, (c) delineate buccal cell assays that have been used successfully, (d) determine whether buccal cell changes correlate with oral cancer as defined in clinicopathologic investigations, and (e) assess the feasibility of developing a high-throughput buccal cell assay for screening smokers for the early detection of oral cancer. The results of the studies reported herein have established that diverse buccal cell changes are associated with smoking and smokeless tobacco. This review documents also that buccal cells have been collected in a noninvasive manner, and repetitively for serial studies, from different sites of the mouth (e.g., cheek, gum, and tongue) and from normal tissue, preneoplastic lesions (leukoplakia), and malignant tumors. Tobacco-associated genetic mutations and nongenetic changes have been reported; a partial listing includes (a) micronuclei, (b) bacterial adherence, (c) genetic mutations, (d) DNA polymorphisms, (d) carcinogen-DNA adducts, and (e) chromosomal abnormalities. Clinical studies have correlated buccal cell changes with malignant tumors, and some oral oncologists have reported that the buccal cell changes are practical biomarkers. Summarily, the literature has established that buccal cells are useful not only for characterizing the molecular mechanisms underlying tobacco-associated oral cancers but also as exfoliative cells that express diverse changes that offer promise as candidate biomarkers for the early detection of oral cancer.

Rangaswamy M; Jones KA; Porjesz B; Chorlian DB; Padmanabhapillai A; Kamarajan C et al. Delta and theta oscillations as risk markers in adolescent offspring of alcoholics. (review). International Journal of Psychophysiology 63(1): 3-15, 2007. (118 refs.)

Background: Visual P300 is consistently lower in alcohol-dependent individuals, their offspring and subjects at risk. Delta and theta event-related oscillations (ERO) are the major contributors to the P300 signal. The total and evoked power in delta and theta bands in the 300 to 700 ins post-stimulus window (corresponding to the zone of P300 maxima) was compared between adolescent offspring of alcoholics (high-risk) and age-matched normal controls (low-risk), to assess the utility of the risk markers. Methods: EEG was recorded during the performance of a visual oddball task. The S-transform algorithm decomposed the EEG signals into different frequency bands and the group differences in total and evoked power in the oscillatory responses during the P300 time window (300 to 700 ins) were analyzed using a multivariate design. Similar analysis was performed on P300 peak amplitude for the target. Results: The high-risk group showed significantly lower parietal post-stimulus evoked and total power in the delta band for targets. A decrease in total power was seen centrally and parietally in the theta band. The P300 peak amplitude in the parietal electrodes was also significantly lower in the high-risk group. Conclusions: The decreased total theta power and total and evoked delta power for visual targets in high risk individuals may serve as an endophenotypic marker in the development of alcoholism and other disinhibitory disorders. The differences seen between the offspring of alcoholics and controls may have a cholinergic basis. The ERO measures appear to be more robust than the P300 amplitude in differentiating the groups.

Rasmusson AM; Wu R; Paliwal P; Anderson GM; Krishnan-Sarin S. A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: A preliminary study. Psychopharmacology 186(3): 473-480, 2006. (71 refs.)

Increases in depressive symptoms during smoking cessation have been associated with risk for relapse. Several studies have linked plasma levels of cortisol and dehydroepiandrosterone (DHEA) or DHEA-sulfate (DHEAS) to depressive symptoms. To determine whether changes in plasma cortisol, DHEA, or DHEAS levels and emergence of depressive symptoms during smoking cessation are associated with smoking relapse. Subjects were healthy non-medicated men and women, aged 39 +/- 12 years, who smoked, on average, 22 cigarettes per day. Depressive symptoms, smoking withdrawal symptoms, and plasma steroid levels were measured before and after 8 days of verified smoking abstinence. Relapse status at day 15 was then determined. In the full sample (n=63), there was a trend for changes in depressive symptoms to be associated with relapse. In the subset of 25 subjects with plasma neuroactive steroid data, there was a significant interaction between the change in the plasma DHEA/cortisol ratio from day 0 to day 8 and relapse status at day 15. This ratio was similar before abstinence, but lower at day 8 in relapsed, compared to abstinent, subjects. Changes in the DHEA/cortisol ratio tended to predict changes in depressive symptoms in the women only. A decrease in the plasma DHEA/cortisol ratio during 8 days of smoking abstinence was associated with relapse over the following week. Further research is needed to fully characterize sex-specific relationships between abstinence-induced changes in neuroactive steroid levels, depressive or withdrawal symptoms, and relapse. Such research may lead to new interventions for refractory smoking dependence.

Sandstrom KA; Rajan TM; Feinn R; Karzler HR. Salty and sour taste characteristics and risk of alcoholism (vol 27, pg 955, 2003) correction. Alcoholism: Clinical and Experimental Research 27(9): 1526-1526, 2003

This is a correction to an article by Sandstrom KA; Rajan TM; Feinn R; Kranzler HR. Salty and sour taste characteristics and risk of alcoholism from Alcoholism: Clinical and Experimental Research 27(6): 955-961, 2003.

Schuckit MA. An overview of genetic influences in alcoholism. (review). Journal of Substance Abuse Treatment 36(1): s5-s14, 2009. (110 refs.)

This review summarizes recent findings from human research regarding genetic influences in alcohol abuse and dependence. Genes explain about 50% of the vulnerabilities leading to heavy drinking and associated problems. Most genetic influences appear to impact at least four prominent intermediate characteristics (phenotypes) that interact with environmental events to produce the alcoholism risk: a flushing response to alcohol; a low level of response to alcohol; personality characteristics that include impulsivity, sensation seeking, and neuronal and behavioral disinhibition; and through psychiatric symptoms. Polymorphisms potentially related to each phenotype have been identified, and studies were conducted to evaluate their characteristics in the context of environmental and psychosocial forces. A search is underway to identify genes that contribute to these phenotypes; the ultimate goals of which are better prediction of how to best prevent heavy drinking and problems, identifying individuals who may respond best to existing treatments, and development of new therapeutic approaches based on the biological underpinnings of alcoholism.

Sexton K; Balharry D; BeruBe KA. Genomic biomarkers of pulmonary exposure to tobacco smoke components. Pharmacogenetics and Genomics 18(10): 853-860, 2008. (67 refs.)

Background: Associations between smoking and the development of tobacco-related diseases in humans have historically been assessed by epidemiological studies. These studies are further complicated by the number of chemicals used in tobacco and individual smoking habits. An alternative approach is required to assess the biological responses. Objective: Toxicogenomics was carried out to identify early molecular markers for events in pulmonary injury resulting from tobacco smoke components (TSC) exposure. Materials and methods EpiAirway-100 cells were exposed at the air/liquid interface to representative particle (nicotine; cadmium) and vapour phase [formaldehyde (FA) and ethyl carbamate] components of cigarette smoke. Microarray technology was used to compare expression profiles of human genes associated with toxicity and drug resistance, from control and TSC-treated respiratory epithelium (n = 5/dose). Results: Using the GEArray 'toxicology and drug resistance' microarray followed by significance analysis of microarray analysis, 42 mRNA transcripts were found to be significantly altered by the TSC exposure. The vapour [ethyl carbamate, FA and particle (nicotine, cadmium)] phase TSC exhibited differential transcriptional responses that could not be attributed to their chemical phase. The transcriptional changes could be classified according to a functional family, where ethyl carbamate, FA and cadmium classified as carcinogens, demonstrated the highest gene homology when compared with the noncarcinogen, nicotine. Discussion: Analysis of the microarray data and further confirmation (reverse transcriptase-PCR) identified three potential biomarkers for TSC-induced injury. These three genes (CYP7A1, HMOX1 and PTGS1) are highly upregulated and have been linked with mechanistic pathways of disease.

Storvik M; Hakkinen M; Tupala E; Tiihonen J. 5-HT1A receptors in the frontal cortical brain areas in Cloninger type 1 and 2 alcoholics measured by whole-hemisphere autoradiography. Alcohol and Alcoholism 44(1): 2-7, 2009. (41 refs.)

Aims: The Cloninger type 1 alcoholics are prone to anxiety, and in many cases patients have begun to use alcohol in order to relieve their anxiety. We have previously reported a decrease of the serotonin transporter density in the perigenual anterior cingulate cortex (pACC) in type 1 alcoholics. The 5-HT1A receptors are the binding sites for anxiolytic drug buspirone. We aimed to investigate the alteration in the density of 5-HT1A receptors, that may also alter the effect of serotonin in the pACC in alcoholics. Methods: The density of the serotonin receptor 5-HT1A among Cloninger type 1 and 2 alcoholics (nine and eight subjects, respectively) and 10 control subjects were determined by postmortem whole-hemisphere autoradiography with WAY-100635. Results: Substantially sparser 5-HT1A (by -31%, P = 0.010) density was observed in the pACC of alcoholic subjects in relation to non-alcoholic comparison subjects. In a secondary analysis for the difference between the alcoholic subtypes and controls, the 5-HT1A density was decreased significantly by -32% (P = 0.015) in the upper level of pACC in type 1 alcoholics. Conclusions: The detected decrease of 5-HT1A receptor density on the pACC suggests further that the serotoninergic system is defected in the so-called affect region, especially in the type 1 alcoholics.

Suadicani P; Hein HO; Gyntelberg F. Wine intake, ABO phenotype, and risk of ischemic heart disease and all-cause mortality: The Copenhagen Male Study-a 16-year follow-up. Alcohol 42(7): 575-582, 2008. (27 refs.)

The association of alcohol intake with ischemic heart disease (IHD) and all-cause mortality may depend on ABO phenotype. We tested this hypothesis in a 16-year follow-up of 3,022 Caucasian men aged 53-74 years without overt cardiovascular disease. Potential risk factors and confounders included were ABO phenotypes, alcohol intake (wine, beer, and spirits), tobacco smoking history, leisure-time, physical activity, social class, and age. During 16 years, 1985-1986 to end of 2001, 197 subjects (6.5%) died due to IHD, and 1,204 (39.8%) from all causes. Among non-O phenotypes (A, B, and AB) significantly fewer men who died due to IHD were wine consumers, 43.9% versus 55.7%, P < .01: with respect to all-cause mortality corresponding figures were 47.0% versus 60.1%, P < .001. No difference was found among men with phenotype O. Among men with phenotype A, compared to alcohol abstainers, in Cox analysis, the hazard ratio (HR) (95% confidence limit) for men drinking up to 8 beverages/wk was 0.5 (0.3-1.02), and among men consuming > 8 beverages/wk (the highest quintile) the HR was 0.3 (0.2-0.8). P < .01, Among men with phenotype O, the association of wine intake with IHD mortality was slightly and not significantly U-shaped. The difference in the predictive role of wine intake between phenotype O and phenotype A men was supported in a statistical test for interaction. A similar association was found for all-cause mortality. The results suggest that the effect of wine intake on IHD and all-cause mortality among middle-aged and elderly men may depend on ABO phenotypes.

Sullivan PF; Kuo PH; Webb BT; Neale MC; Vittum J; Furberg H et al. Genomewide linkage survey of nicotine dependence phenotypes. Drug and Alcohol Dependence 93(3): 210-216, 2008. (46 refs.)

Background: A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses. Methods: We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerstrom Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods. Findings: For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions-an 11 cM region on chr7 (D7S2252-D7S691, empirical p = 0.0006) and an 8 cM region on chrl 8 flanking D18S63 (empirical p=0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND. Interpretation: Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related C phenotypes.

Sun LM; Konig IR; Jacobs A; Seitz HK; Junghanns K; Wagner T et al. Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases. Alcoholism: Clinical and Experimental Research 29(5): 788-793, 2005. (37 refs.)

Background: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. Methods: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n = 98), chronic pancreatitis (n = 98), alcoholic liver cirrhosis (n = 151), and alcohol abuse without gastrointestinal disease (n = 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. Results: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis, In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. Conclusions: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.

Suresh S; Porjesz B; Chorlian DB; Choi K; Jones KA; Wang KM; Stimus A; Begleiter H. Auditory P3 in female alcoholics. Alcoholism: Clinical and Experimental Research 27(7): 1064-1074, 2003. (98 refs.)

Background: The P3 (P300) has been considered to be a phenotypical marker of the risk for alcoholism. Although reductions in visual P3 in male and female alcoholics have been replicated, studies of auditory target P3 have been inconsistent. Our objective was to study the magnitude of auditory P3 reduction in female alcoholics and to establish the association between P3 reduction and alcoholism while taking into account comorbid depression and psychoactive drug dependence. The characteristics of P3 reduction were further examined by studying the reduction in family history-positive and -negative individuals. Methods: Auditory target P3s recorded from 61 scalp electrodes in female alcoholics (n = 71) were compared with P3s from female controls (n = 159) ranging in age from 18 to 50 years. The amplitudes and latencies were statistically analyzed, by using repeated-measures ANOVA, in six regional electrode arrays and at representative electrode sites, with age and comorbid depression as covariates. The effects of family density and clinical variables such as depression and drug dependence were also examined with correlation analysis. Results: Alcoholic women had significantly lower P3 amplitudes in all six regions and at midline electrode sites. The reductions were not associated with comorbid depression, as shown by low correlations and similar P3 amplitudes at Pz in female alcoholics with and without depression. The P3 amplitudes in women with a high family density were smaller than those in women with a low family density of alcohol dependence. Drug dependency did not influence P3 amplitude, as shown by similar responses in drug-dependent and non-drug-dependent alcoholic women. Conclusions: These findings highlight the significance of P3 reductions associated with alcoholism in women, independently of comorbid depression. Family density effects further support the evidence that these findings are heritable. These results suggest that P3 can be considered as a phenotypical marker of vulnerability to alcoholism in women.

Taylor C; Nash J; Rich A; Lingford-Hughes A; Nutt D; Potokar J. Assessment of GABA(A) benzodiazepine receptor (GBzR) sensitivity in patients with alcohol dependence. Alcohol and Alcoholism 43(6): 614-618, 2008. (30 refs.)

Aim: The aim of this study was to measure GABA(A) benzodiazepine receptor (GBzR) sensitivity in alcohol-dependent patients and compare with matched non-dependent drinkers. Methods: Nine abstinent alcohol-dependent male patients, age matched with nine male non-dependent social drinkers, received an intravenous infusion of midazolam. Objective (saccadic eye movement slowing) and subjective (visual analogue scales) measurements were recorded at 15-min intervals for 2 h. Results: There were no differences in objective or subjective measures. Conclusions: Our hypothesis that patients with alcohol dependence would have less slowing of their eye movements in response to this challenge, reflecting reduced GBzR sensitivity, was not confirmed. The reasons for this could mean that GBzR function returns to normal with abstinence, or that this paradigm is unable to measure the subtle subtype-specific changes in GBzR sensitivity that occur following dependent alcohol use.

Venkatasubramanian G; Anthony G; Reddy US; Reddy VV; Jayakumar PN; Benegal V. Corpus callosum abnormalities associated with greater externalizing behaviors in subjects at high risk for alcohol dependence. Psychiatry Research: Neuroimaging 156(3): 209-215, 2007. (28 refs.)

Subjects at high risk for alcoholism have a greater propensity for externalizing behaviors and brain volume reductions of possible neurodevelopmental origin. Morphometric deficits in the corpus callosum (CC), which might reflect this neurodevelopmental abnormality, have been reported in other externalizing disorders such as attention deficit hyperactivity disorder, but not in subjects at high risk for alcoholism. The objective of the current study was to evaluate the CC morphometry in subjects at high risk for alcoholism. Magnetic resonance images of the CC in high-risk subjects (n=20) were compared with those of low-risk subjects matched to the high-risk subjects for age, sex, and handedness (n=20). Mid-sagittal areas of the CC, germ, body, isthmus and splenium were measured based on Witelson's method with good inter- and intra-rater reliability. Externalizing behaviors were assessed using the Semi-Structured Assessment for Genetics of Alcoholism-II. Total CC, genu and isthmus areas were significantly smaller in high-risk than low-risk subjects after controlling for age and intracranial area. The total externalizing symptoms score had a significant negative correlation with genu and isthmus areas. Smaller CC areas and their negative association with externalizing behaviors may represent yet another marker of susceptibility to alcoholism in high-risk subjects.

Wall TL; Carr LG; Ehlers CL. Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in native American mission Indians. American Journal of Psychiatry 160(1): 41-46, 2003. (59 refs.)

Objective: Two alcohol dehydrogenase genes (ADH2 and ADH3 on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorphisms. The goal of this study was to determine whether any associations exist between the ADH2, ADH3, and ALDH2 polymorphisms and alcohol dependence in a group of Native Americans. An additional goal was to determine if any associations exist between these polymorphisms and the endophenotype, maximum number of drinks ever consumed in a 24-hour period. Method: Mission Indian adults (N=340) were recruited for participation from reservations in southern California. Each participant completed an interview with the Semi-Structured Assessment for the Genetics of Alcoholism. A blood sample was collected from each participant for genotyping at the ALDH2, ADH2, and ADH3 loci. Results: Sixty percent of all participants (72% of men and 53% of women) met life-time DSM-III-R criteria for alcohol dependence. A significant difference in the ADH2 allele distributions was found between alcohol-dependent and non-alcohol-dependent participants. Those with alcohol dependence were significantly less likely to have the ADH2*3 allele (odds ratio=0.28) and significantly more likely to have the ADH2*1 allele (odds ratio=2.00) than those who were not alcohol dependent. Individuals with ADH2*3 reported a lower number of maximum drinks ever consumed in a 24-hour period, compared to those without this allele. Conclusions: These results are consistent with genetic linkage studies showing protective associations for alcohol dependence and related behavior on chromosome 4 and suggest that ADH2 polymorphisms may account for these findings. These results also highlight the utility of evaluating protective factors in populations with high rates of alcohol dependence.

Wurst FM; Alexson S; Wolfersdorf M; Bechtel G; Forster S; Alling C et al. Concentration of fatty acid ethyl esters in hair of alcohlics: Comparison to other biological state makers and self reported-ethanol intake. Alcohol and Alcoholism 39(1): 33-38, 2004. (42 refs.)

Aims: In a variety of clinical and forensic situations long term use of alcohol must be monitored. In this project we explore the utility of fatty acid ethyl esters (FAEE) in this regard. Additionally, we propose a cut-off value of FAEE to distinguish teetotallers/moderate/social drinkers from alcoholics or individuals drinking at harmful levels. Patients and methods: FAEE levels from 18 alcohol-dependent patients in detoxification were contrasted with those of 10 social drinkers and 10 teetotallers. FAEE in hair were determined, using headspace solid phase microextraction and gas chromatography mass spectrometry. CFAEE, as sum of the concentrations of four esters, was compared to a major FAEE, ethyl palmitate. PEth was measured in heparinized whole blood with a high pressure liquid chromatography (HPLC) method. Drinking validation criteria include self reports, phosphatidyl ethanol (PEth) in whole blood as well as the traditional markers of heavy drinking, gamma glutamyl transpeptidase (GGT), mean corpuscular volume (MCV) and carbohydrate deficient transferrin (CDT). Results: Receiver-operating characteristic (ROC) curve analysis for CFAEE, indicated a sensitivity of 100% and a specificity of 90% for a cut-off of 0.29 ng/mg. By using a cut-off of 0.4 ng/mg, FAEE identified 94.4% correctly. FAEE and ethyl palmitate were significantly associated (r = 0.945; P < 0.001) as were CFAEE and PEth (r = 0.527; P = 0.025). No significant correlation was found between FAEE and total grams of ethanol consumed last month, blood-alcohol concentration at admission to the hospital, CDT, MCV, or GGT. Among the serum and blood markers, %CDT identified 47.1%, MCV 38.8% and GGT 72.2% of patients with chronic intake of higher amounts of ethanol correctly, whereas PEth achieved 100% accuracy. Conclusions: The data suggest that FAEE is a potentially valuable marker of chronic intake of high quantities of ethanol. Furthermore, the results indicate that a reasonable and provisional FAEE cut-off to distinguish between social/moderate and heavy drinking/alcoholism in hair is 0.4 ng/mg.

Young EM; Mahler S; Chi H; de; Wit H. Mecamylamine and ethanol preference in healthy volunteers. Alcoholism: Clinical and Experimental Research 29(1): 58-65, 2005. (43 refs.)

Background: Recent evidence suggests that some of the behavioral effects of alcohol may be mediated through actions on nicotinic acetylcholine receptors. Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduces alcohol preference and consumption in alcohol-preferring rats, and in humans, mecamylamine dampens some of the subjective, or mood-altering, effects of alcohol. This experiment was designed to investigate the effects of mecamylamine on consumption of alcohol in healthy social drinkers. Methods: Healthy volunteers (12 men, 12 women) participated in a choice procedure in which they chose between an alcoholic beverage and money (low, medium, or high amounts) after pretreatment with mecamylamine (7.5 or 15 mg) or placebo. Outcome measures were the number of alcoholic beverages consumed and the subjective effects of alcohol. Results: Mecamylamine (15 mg) decreased blood alcohol levels (BALs) after a small fixed dose of alcohol (0.2 g/kg). Even when the lower BALs were taken into account, mecamylamine reduced ratings of stimulation after alcohol (Addiction Research Center Inventory A scale). Mecamylamine did not significantly reduce choice for alcohol versus money. However, there was a tendency for the drug to decrease alcohol choice among participants who reported the greatest stimulant-like effects from alcohol. Conclusion: These results provide only limited support for the idea that nicotinic acetylcholine receptors are involved in the rewarding effects of alcohol.