bluuebunny/crossref_metadata_2025 huggingface dataset:
An Examination Between Single‐Parent Family Background and Drunk Driving in Adulthood: Findings From The Northern Finland 1966 Birth Cohort
Authors: Sauvola Anu , Miettunen Jouko , Järvelin Marjo‐Riitta , Räsänen Pirkko
Published: April 2006

Background: It has been suggested earlier that parental loss could be an important risk factor for alcoholism in adulthood. We e‐plored the association between different types of childhood families with later alcohol‐related problems of the offspring, in particular drunk driving.

Methods: We used a large, prospectively collected general population birth cohort database (n= 10,934), the Northern Finland 1966 Birth Cohort. Linked with the National crime register, it provided information on drunk driving offenses known to the police that involved persons 15 to 32 years of age (n= 432). Type of family was categorized into five subgroups: two‐parent family and four types of single‐parent families (single‐parent all the time, single‐parent at birth, parental death, parental divorce). The information about family type was obtained from questionnaires given to the mothers during mid‐pregnancy and at the time of the 14‐year follow‐up.

Results: Single‐parent family during childhood significantly increased the risk of drunk driving in adulthood among both males and females. Males who were born in single‐mother families were at the highest risk of drunk driving offenses in adulthood (adjusted OR 2.4; 95% CI 1.4–4.2). The association between single‐parent family and drunk driving among males was seen in all types of single‐parent families e‐cept for parental death.

Conclusions: Results suggest that growing up in a single‐parent family is a potentially powerful predictor of adult alcohol‐related problems, i.e., early‐onset, late‐onset, and recidivistic drunk driving.
Concurrent Alcoholism and Social Anxiety Disorder: A First Step Toward Developing Effective Treatments
Authors: Randall Carrie L. , Thomas Suzanne , Thevos Angelica K.
Published: April 2006

Background: Social an‐iety disorder (also called social phobia) is an an‐iety disorder in which affected individuals fear the scrutiny of others. Clinical reports suggest that individuals with social an‐iety disorder often use alcohol to alleviate an‐iety symptoms, a practice that leads to alcohol abuse and/or dependence in appro‐imately 20% of affected individuals. The present study investigated whether simultaneous treatment of social phobia and alcoholism, compared with treatment of alcoholism alone, improved alcohol use and social an‐iety for clients with dual diagnoses of social an‐iety disorder and alcohol dependence.

Methods: The design was a two‐group, randomized clinical trial that used 12 weeks of individual cognitive behavioral therapy for alcoholism only (n= 44) or concurrent treatment for both alcohol and social anxiety problems (n= 49). Outcome data were collected at the end of 12 weeks of treatment and at 3 months after the end of treatment.

Results: Results with intent‐to‐treat analyses showed that both groups improved on alcohol‐related outcomes and social an‐iety after treatment. With baseline scores covaried, there was a significant effect of treatment group on several drinking measures. Counter to the hypothesis, the group treated for both alcohol and social an‐iety problems had worse outcomes on three of the four alcohol use indices. No treatment group effects were observed on social an‐iety indices.

Conclusions: Implications for the staging of treatments for coe‐isting social phobia and alcoholism are discussed, as well as ways that modality of treatments might impact outcomes.
Identification of Heavy Drinkers By Using the Early Detection of Alcohol Consumption Score
Authors: Harasymiw James W. , Bean Pamela
Published: April 2006

Background: The objective of this study was to evaluate the use of routine blood chemistry and hematology tests to detect heavy drinkers among ambulatory subjects. Heavy drinkers were defined as subjects who consumed an average of four or more standard drinks per day if male and an average of three or more standard drinks per day if female, for at least 1 month before sample collection (1 standard drink = 15 ml of absolute ethanol).

Methods: A routine blood chemistry panel and the demographic factors of age, sex, and ethnicity were evaluated by using linear discriminant function (LDF) analysis to classify subjects as heavy drinkers or light drinkers. The classification was validated by comparison with drinking patterns established by standardized questionnaire and interview. Subjects (n= 807) were males and females with known drinking patterns recruited from 25 centers that included detoxification and rehabilitation institutions, churches, and community groups in the Milwaukee and Boston areas.

Results: With LDF, 88% of the heavy drinkers and 92% of the light drinkers were correctly identified by the Early Detection of Alcohol Consumption test. The LDF performed the best when used to identify heavy drinking in ages 40 and above, a group that showed 84% (120 of 143) sensitivity at 97% (152 of 157) specificity. Performance in females showed 73% (76 of 104) sensitivity at 94% (129 of 137) specificity, rates higher than obtained with any single biochemical marker previously examined. Receiver operating characteristic plot analysis showed areas under the curve of 0.94 for females and 0.95 for males (p < 0.0001).

Conclusions: The Early Detection of Alcohol Consumption score is a practical laboratory screen for detecting heavy drinking based on blood constituents ordered routinely in clinical settings.
Use of Genetic Analyses to Refine Phenotypes Related to Alcohol Tolerance and Dependence
Authors: Crabbe John C.
Published: April 2006

Various explanations for the dependence on alcohol are attributed to the development of tolerance to some of alcohol's effects, alterations in sensitivity to its rewarding effects, and unknown pathologic consequences of repeated exposure. All these aspects of dependence have been modeled in laboratory rodents, and these studies have consistently shown a significant influence of genetics. Genetic mapping studies have identified the genomic location of the specific genes for some of these contributing phenotypes. In addition, studies have shown that some genes in mice seem to affect both alcohol self‐administration and alcohol withdrawal severity: genetic predisposition to high levels of drinking covaries with genetic predisposition to low withdrawal severity, and vice versa. Finally, the role of genetic background on which genes are expressed is important, as are the specifics of the environment in which genetically defined animals are tested. Understanding dependence will require disentangling the multiple interactions of many contributing phenotypes, and genetic analyses are proving very helpful. However, rigorous understanding of both gene‐gene and gene‐environment interactions will be required to interpret genetic experiments clearly.
A Genome‐Wide Search for Genes That Relate to a Low Level of Response to Alcohol
Authors: Schuckit M. A. , Edenberg H. J. , Kalmijn J. , Flury L. , Smith T. L. , Reich T. , Bierut L. , Goate A. , Foroud T.
Published: April 2006

Background: The low level of response (LR) to alcohol is genetically influenced in both humans and animals, and a low LR is a characteristic of offspring of alcoholics that has been reported to predict alcoholism 10 and 15 years later. The genes that contribute to a low LR have not yet been identified.

Methods: A 12‐item questionnaire that measures LR, the Self Rating of the Effects of Alcohol (SRE) instrument, was filled out by 745 individuals from the Collaborative Study on the Genetics of Alcoholism (COGA) for whom genetic material was available. These subjects were genotyped by using 336 markers with an average heterozygosity of 0.74 and an average intermarker distance of 10.5 cM. Both quantitative and qualitative nonparametric, sib‐pair analyses were carried out for the SRE measure related to early drinking experiences.

Results: Correlations of SRE scores across related individuals were significant and between 0.16 and 0.22 for most values, compared with nonsignificant correlations of 0.03 or less among unrelated individuals. Linkage analyses performed by using the FIRST 5 variables (first five times alcohol is consumed) identified four chromosomal regions with lod scores ≥2.0 whose maximum was also near a marker. One of these chromosomal regions previously was linked to alcohol dependence in the COGA sample.

Conclusions: These data document the familial nature of a low LR to alcohol as measured by the SRE and suggest several chromosomal regions that might contribute to the phenomenon.
Mismatch Negativity in Subjects at High Risk for Alcoholism
Authors: Lei Zhang Xiao , Cohen Howard L. , Porjesz Bernice , Begleiter Henri
Published: April 2006

Background: Evidence from P300 studies in both alcohol‐dependent and high‐risk (HR) individuals suggests that the reduced P300 amplitudes that often characterize these individuals may reflect a deficit in inhibition (hyperexcitability) in the central nervous system. In this context, the mismatch negativity (MMN) was investigated in the male and female HR offspring of alcohol‐dependent fathers and a mixed‐sex, low‐risk (LR) control group.

Methods: As subjects read popular materials, they received a random sequence of 500 binaurally presented tones of 600 Hz and 1600 Hz. The designation of the rare stimulus (n= 60 trials) and frequent stimulus (n= 440 trials) was alternated across subjects.

Recordings of MMN were made from 61 electrodes; risk group comparisons were restricted to the five frontal midline electrodes: Fpz, Afz, Fz, Fcz, and Cz. The MMN was obtained by calculating the integral of the area under the curve for both the frequent and rare waveforms over an interval from 100 to 190 msec and then subtracting the former from the latter.

Results: The primary observation was that MMN responses in the HR group were significantly larger than those in the LR group. In addition, both LR and HR individuals manifested differential responses to the rare and frequent stimuli, and MMN responses in both groups were largest at Fcz and smallest at Fpz.

Discussion: The results indicate that individuals at high risk for alcoholism differ electrophysiologically from LR controls. These differences were manifested as larger magnitudes of the MMN. The findings suggest the possibility that as measured by the MMN, individuals at high risk for alcoholism may be characterized by a deficit in inhibition (excessive neural excitation). The presence of these preexisting central nervous system states may lead to ethanol use for self‐medication, which then may facilitate the development of both tolerance to and dependence on ethanol.
Serotonergic Dysfunction, Negative Mood States, and Response to Alcohol
Authors: Heinz Andreas , Mann Karl , Weinberger Daniel R. , Goldman David
Published: April 2006

Background: Dysfunction of central serotonergic neurotransmission has been implicated in the pathogenesis and maintenance of alcoholism. Serotonergic dysfunction may be associated with three behavior patterns relevant for alcoholism: impulsive aggression, negative mood states, and a low response to alcohol intake.

Methods: We reviewed the literature on the psychopathological correlates of serotonergic dysfunction and focused on studies that assess the interaction between negative mood states and alcohol response.

Results: Prospective studies in nonhuman primates that underwent early separation stress found an association between a low serotonin turnover rate and the disposition to excessive alcohol intake and impulsive aggression. These findings seem to be relevant for a subgroup of alcoholics with a low serotonin turnover rate and antisocial personality traits. Cross‐sectional data in humans also support a relationship between reduced serotonergic neurotransmission and aggressive behavior and indicate that the association of serotonergic dysfunction and aggression may be mediated by negative mood states. This hypothesis is in accordance with a large body of data linking anxiety and depression to serotonergic dysfunction. In human alcoholics, brain imaging has detected a reduction in serotonin transporter availability in association with depression. Serotonin transporter availability seems to be related to reduced GABA‐ergic sedation and the acute response to alcohol intake, an important predictor of subsequent development of alcohol dependence.

Conclusions: Several lines of evidence point to a relationship between serotonergic dysfunction, negative mood states, and excessive alcohol intake, which may be mediated in part by reduced alcohol‐induced sedation.
Ethanol Decreases Expression of p21 and Increases Hyperphosphorylated pRb in Cell Lines of Squamous Cell Carcinomas of the Head and Neck
Authors: Hager Gudrun , Formanek Michael , Gedlicka Claudia , Knerer Birgit , Kornfehl Johannes
Published: April 2006

Background: Alcohol increases the risk of cancers of the upper aerodigestive tract, but the biological mechanisms of this ethanol effect are still unclear. We recently reported that ethanol is able to induce in vitro proliferation accompanied by an increased number of cells in the S phase of the cell cycle in squamous cell carcinoma cell lines of the head and neck (SCCHN). In the current study we investigated the influence of ethanol over a limited period of time (96 hr) on cell cycle–regulating proteins involved in G1/S phase transition.

Methods: Synchronized cells of SCCHN cell lines JPPA (larynx) and SCC 9 and SCC 25 (tongue), as well as HaCaT (human immortalized keratinocytes)—used as a control—were cultured for 96 hr in the presence or absence of ethanol (10−3M). At several time intervals the expression of cyclin D1 and p21 and the phosphorylation status of the retinoblastoma protein (pRb) were determined by Western or Northern Blot analysis, or both.

Results: Ethanol had no influence on the protein expression of cyclin D1. In contrast, a distinct downregulation of p21 at the protein as well as the mRNA level could be detected. Furthermore, as a downstream event, the hyperphosphorylated form of the pRb increased.

Conclusions: In the acute alcohol in vitro experiments, the marked downregulation of the important cell cycle inhibitor p21 and the corresponding increase of hyperphosphorylated pRb accelerate the progression of cells from the G1 to the S phase in the cell cycle. The importance of these data and their relevance to in vivo conditions remain speculative, but it could be a critical step in the multistep process of SCCHN carcinogenesis induced by ethanol.
Gender Differences in Pharmacokinetics of Alcohol
Authors: Baraona Enrique , Abittan Chaim S. , Dohmen Kazufumi , Moretti Michelle , Pozzato Gabriele , Chayes Zev W. , Schaefer Clara , Lieber Charles S.
Published: April 2006

Background: The enhanced vulnerability of women to develop alcohol‐related diseases may be due to their higher blood alcohol levels after drinking, but the mechanism for this effect is debated.

Methods: Sixty‐five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First‐pass metabolism was quantified (using Michaelis‐Menten kinetics) as the route‐dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 μCurie of technetium‐labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for γ‐ADH (acetaldehyde) and for ς‐ADH (m‐nitrobenzaldehyde) and a specific reaction of χ‐ADH (glutathione‐dependent formaldehyde dehydrogenase).

Results: Women had less first‐pass metabolism than men when given 10% or 40%, but not 5%, alcohol. This was associated with lower gastric χ‐ADH activity; its low affinity for ethanol could explain the greater gender difference in first‐pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route‐dependent effects.

Conclusions: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of χ‐ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration‐dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.
Quantitative Autoradiography of Mu‐Opioid Receptors in the CNS of High–Alcohol‐Drinking (HAD) and Low–Alcohol‐Drinking (LAD) Rats
Authors: Learn Jennifer E. , Chernet Eyassu , McBride William J. , Lumeng Lawrence , Li Ting‐Kai
Published: April 2006

Background: The binding of [3H]DAMGO to mu‐opioid sites was measured in the CNS of selectively bred high–alcohol‐drinking (HAD) and low–alcohol‐drinking (LAD) rats to test the hypothesis that high alcohol preference is associated with higher densities of mu‐opioid receptors.

Methods: Adult, alcohol‐naïve male HAD and LAD rats from replicate line 1 were decapitated and their brains frozen in isopentane. Brain sections were incubated with 5 nM [3H]DAMGO, and nonspecific binding was determined in the presence of unlabeled DAMGO. Films were exposed for 60 days, then analyzed using quantitative autoradiography.

Results: The densities of [3H]DAMGO binding sites were measured within subregions of neocortex, limbic system, basal ganglia, diencephalon, and brainstem. LAD rats had significantly higher [3H]DAMGO binding (10–30%) than HAD rats within the anterior dorsal hippocampus (CA2), posterior hippocampus (dorsal CA1, and ventral CA1, CA3, and dentate gyrus), thalamus (medial dorsal, lateral, medial dorsal, central, ventral lateral, ventral medial, and ventral medial geniculate nuclei), habenula, and amygdala. No significant interline differences were found in the prefrontal, cingulate, frontal, parietal, temporal, occipital or entorhinal cortices, olfactory tubercle, nucleus accumbens, lateral septum, ventral tegmental area, hypothalamus, caudate‐putamen, substantia nigra, claustrum, central gray, or superior colliculus.

Conclusions: The present findings with the HAD and LAD lines do not support the hypothesis that high alcohol preference is associated with higher densities of CNS mu‐opioid receptors. Instead, the present results, in combination with previously published findings, suggest that the mu‐opioid system may play a complex role in regulating high–alcohol‐drinking behavior.
Sociodemographic and Individual Predictors of Alcohol Policy Attitudes: Results From a US Probability Sample
Authors: Latimer William W. , Harwood Eileen M. , Newcomb Michael D. , Wagenaar Alexander C.
Published: April 2006

Objective: Public views on alcohol policies have facilitated legislative change. Given limited resources, however, policy makers and prevention advocates cannot make haphazard attempts to mobilize public resources. This investigation reports sociodemographic and individual traits predicting attitudes on alcohol policies designed to reduce underage alcohol consumption. Previous studies have examined single‐item measures of alcohol policy. We examined predictors of multi‐item scales measuring five core dimensions of alcohol policy.

Methods: A survey of public attitudes on alcohol policies was administered to a US national probability sample of 7021 adults.

Results: Women, infrequent drinkers, and adults with greater knowledge about or concern for youth exhibited the greatest support across five alcohol policy scales. Older adults favored policies that restrict alcohol use in public places, whereas younger adults favored an increase in alcohol taxes to address underage alcohol use.

Conclusions: Individual factors such as alcohol use frequency and concern for youth explained larger proportions of variance in alcohol policy attitudes than did sociodemographic factors. Consistent with previous research, political orientation, parental status, employment status, and marital status did not predict attitudes on alcohol policy.
Pro‐ and Anti‐Inflammatory Gene Expression in the Murine Small Intestine and Liver After Chronic Exposure to Alcohol
Authors: Fleming Sherry , Toratani Satoshi , Shea‐Donohue Terez , Kashiwabara Yoshiko , Vogel Stefanie N. , Metcalf Eleanor S.
Published: April 2006

Background: Endotoxin has been proposed to play a primary role in ALD, by initiating an inflammatory cascade within the liver. Although the source of these cytokines has been presumed to be circulating monocytes or tissue macrophages, ethanol‐induced, nonhepatic sources of soluble mediators recently have been identified. One potential, but not clearly defined, extrahepatic source of cytokines in ALD is the intestine. In the current study, we hypothesized that alcohol would alter cytokine expression within the small intestine of mice exposed to ethanol and that LPS would alter levels of cytokine expression even more dramatically.

Methods: Mice were fed a modified Lieber‐DeCarli liquid ethanol or control diet for up to 14 days prior to injecting either saline or LPS. Plasma alanine aminotransferase (ALT) and cytokine levels, histology, and RT‐PCR of pro‐ and anti‐inflammatory cytokine gene expression were determined from distal ileum and liver samples. Translocation of intestinal bacterial flora also was assessed.

Results: Ethanol exposure upregulated basal gene expression of IL‐1β, TNF‐α, IL‐6, and iNOS in the distal ileum, but similar effects of ethanol on the liver were not observed. In contrast, LPS challenge of ethanol‐exposed mice increased intestinal gene expression of some cytokines, but decreased expression of others. These effects were not associated with bacterial translocation. Also, ethanol alone induced a modest increase in both ICAM‐1 and TLR4 mRNA expression in the intestine, but expression of both molecules was inhibited in mice that received both ethanol and LPS. Finally, whereas basal levels of hepatic IL‐11 mRNA were not elevated by exposure to ethanol, intestinal IL‐11 mRNA levels were increased more than100‐fold.

Conclusions: These studies are the first to show that ethanol affects cytokine gene expression in the ileum and identifies the ileum as a potential target for ethanol effects. In addition, our results suggest that IL‐11 expression may be enhanced in the intestine to help repair or protect this organ from alcohol‐induced damage. Collectively, these studies suggest that both pro‐ and anti‐inflammatory soluble mediators in the intestine maintain and exacerbate the local hepatic response to ethanol.
Responsivity and Development of Tolerance to the Motor Impairing Effects of Moderate Doses of Ethanol in Alcohol‐Preferring (P) and ‐Nonpreferring (NP) Rat Lines
Authors: Bell Richard L. , Stewart Robert B. , Woods James E. , Lumeng Lawrence , Li Ting‐Kai , Murphy James M. , McBride William J.
Published: April 2006

Background: Research comparing the alcohol‐preferring (P) and ‐nonpreferring (NP) rat lines has detected an apparent association between ethanol preference and lower responsivity to ethanol, as well as the capacity to develop and maintain tolerance to ethanol's effects. However, past studies of tolerance to ethanol's effects generally involved relatively high doses. The present study examined recovery from functional impairment induced by moderate doses of ethanol after a single dose (responsivity) and after multiple doses (development of tolerance) in the P and NP rat lines.

Method: Adult female P and NP rats were trained, for 5 consecutive days, to stay on an oscillating bar for 120 sec. Rats were then assigned to one of three groups to receive 1.0, 1.25, or 1.5 g/kg ethanol for 5 consecutive test days. Rats were tested each day at 15‐min intervals, following intraperitoneal injection, until recovery to the 120 sec criterion.

Results: On the first test day, NP rats took longer to recover to criterion than the P rats following the 1.0 and 1.25 g/kg doses, whereas at the 1.5 g/kg dose no line difference was evident. Trunk blood alcohol concentrations (BACs), associated with time to recovery, indicated higher values for the P than NP rat on day 1 following injection of the two lower doses. Compared to day 1, NP rats demonstrated significantly shorter times to recovery beginning on day 2 following injections of the 1.0 and 1.25 g/kg doses. However, NP rats did not show significantly different recovery times on days 2–5 compared to day 1 following injection of the 1.5 g/kg dose. The shorter recovery times at the 1.0 and 1.25 g/kg doses were associated with BACs at recovery on day 3 being equal to or greater than values obtained on day 1. In contrast, compared to day 1, P rats did not show shorter recovery times until days 3 and 5 following the 1.0 and 1.25 g/kg doses, respectively. However, P rats did demonstrate shorter recovery times on day 2 and higher BACs on day 3 compared to day 1 following the 1.5 g/kg dose.

Conclusion: With regard to motor impairment, lower responsivity to moderate doses of ethanol may be a factor associated with high alcohol‐seeking behavior. The present results confirm past research supporting an association between ethanol preference and low ethanol responsivity but at doses that are more reflective of those self‐administered by P rats.
Chronic Alcohol Consumption and Cerebral Indices of Oxidative Stress: Is There a Link?
Authors: Götz M. E. , Janetzky B. , Pohli S. , Gottschalk A. , Gsell W. , Tatschner T. , Ransmayr G. , Leblhuber F. , Gerlach M. , Reichmann H. , Riederer P. , Böning J.
Published: April 2006

Background: It is still difficult to define the biochemical mechanisms that cause alterations in neuronal function and plasticity and neuronal cell loss in the brains of alcohol‐dependent patients.

Methods: To evaluate the extent of cerebral alcohol‐induced oxidative stress ex vivo, we investigated the levels of glutathione (GSH), its oxidation product glutathione disulfide (GSSG, produced by GSH‐peroxidases), and the activities of catalase and superoxide dismutases (SOD). In addition, selected brain regions from up to 22 subjects (versus controls) were studied post mortem to compare the amount of oxidized DNA‐base 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) with levels of deoxyguanosine (dG) in mitochondrial and nuclear DNA.

Results: The most prominent findings showed significantly decreased GSH/(GSH+2GSSG) molar redox (oxidation‐reduction) ratios in the corpus mamillare and cerebellum, which appeared due to an increase in GSSG caused by chronic alcohol intake. Catalase activity was increased in only the frontal cortex, whereas decreased catalase activity was found in the corpus callosum. In contrast, neither copper‐zinc‐superoxide dismutase (CuZnSOD) and manganese‐superoxide dismutase (MnSOD) activities nor 8‐OHdG/dG molar ratios were altered, although a tendency toward higher OHdG/dG ratios in temporal and parietal cortex from alcohol‐dependent patients could be detected when mitochondrial DNA was analyzed selectively.

Conclusions: We propose that decreased brain GSH/(GSH+2GSSG) molar redox (oxidation‐reduction) ratios in alcohol‐dependent patients may reflect neural impairment due to increased peroxide production after chronic alcohol consumption. However, future experiments, investigating the activities of enzymes and cofactors involved in GSH synthesis and metabolism in the human brain, will have to validate the specificity of these results for oxidative stress.
Genetic Correlations Between Initial Sensitivity to Ethanol and Brain cAMP Signaling in Inbred and Selectively Bred Mice
Authors: Kirstein Shelli L. , Tabakoff Boris
Published: April 2006

Background: Several lines of evidence have suggested a role for cAMP (adenosine 3′,5′‐cyclic monophosphate) signaling in the acute and chronic effects of ethanol. This study investigated whether there is a genetic correlation between cAMP synthesis in the brain and the acute effects of ethanol [alcohol sensitivity or acute functional tolerance (AFT)].

Methods: By using nine inbred strains of mice, we measured initial sensitivity and AFT to ethanol with a test of balance on a dowel. Initial sensitivity was defined by the blood ethanol concentration (BEC0) at the loss of balance on a dowel after an ethanol injection [1.75 g/kg intraperitoneally (ip)]. When mice were able to regain balance on the dowel, BEC1 was determined, and a second ethanol injection was given (2 g/kg ip). Upon final regaining of balance, BEC2 was determined. AFT was defined by the difference between BEC1 and BEC2 (AFT =ΔBEC = BEC2− BEC1). Cyclic AMP synthesis was measured in whole‐cell preparations in the cerebellum and other brain areas of mice of the nine inbred strains.

Results: Significant differences in BEC0 and AFT were seen among the mice of the nine inbred strains. Cerebellar basal and forskolin‐ and isoproterenol‐stimulated cAMP production differed significantly between the strains, and BEC0 was found to correlate significantly with forskolin‐ and isoproterenol‐stimulated cAMP accumulation in the cerebellum (r= 0.70 and 0.94, respectively). When we measured cAMP production in mesencephalic and telencephalic tissue in three strains of mice that differed significantly in isoproterenol‐stimulated cAMP accumulation in the cerebellum, significant differences between strains were found only in telencephalic tissue. The relative relationship between the rank order of the three strains for cAMP accumulation in the telencephalon and initial sensitivity to ethanol was identical to that seen with the cerebellum. However, AFT did not correlate with cAMP accumulation in the cerebellum or any other brain area tested.

Conclusions: These results suggest that cAMP‐generating systems of the cerebellum and possibly the brain areas contained in telencephalic tissues (e.g., basal ganglia) may have an important relationship to an animal's initial sensitivity to the incoordinating effects of ethanol.
Combining Ondansetron and Naltrexone Treats Biological Alcoholics: Corroboration of Self‐Reported Drinking by Serum Carbohydrate Deficient Transferrin, A Biomarker
Authors: Ait‐Daoud Nassima , Johnson Bankole A. , Javors Martin , Roache John D. , Zanca Nursen A.
Published: April 2006

Background: Recently, we showed by using self‐report that combining ondansetron (4 μg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early‐onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self‐reported differences in drinking would be corroborated by measurements of serum carbohydrate‐deficient transferrin (CDT) level, a sensitive, reliable, and well‐validated marker of transient alcohol consumption.

Method: An 8‐week double‐blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 μg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8.

Results: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 ± 0.076) compared with the placebo group (group mean, 1.82 ± 0.113), as evidenced by a main effect of group [F (1,15) = 7.2, p= 0.017; effect size = 0.32], visit [F (1,16) = 11.2, p= 0.004; effect size = 0.41], and an interaction between group and visit [F (1,16) = 27.54, p < 0.001; effect size = 0.63].

Conclusions: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self‐reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs.
The Identification of Alcohol Intoxication by Police
Authors: Brick John , Carpenter John A.
Published: April 2006

Background: The identification of alcohol intoxication by police, bartenders, social hosts, and potential passengers is an important issue in the prevention of alcohol‐related driving accidents. This study examines the ability of police officers to correctly identify and make ratings of the sobriety of target drinkers presented on video.

Methods: Raters were asked to determine (1) whether the target drinker had been drinking alcohol, (2) whether it was “okay” to serve the target another drink, and (3) whether the target drinker was “okay” to drive. A rater confidence score for each target evaluated, as well as demographic characteristics about the raters, was obtained.

Results: Drinkers were accurately targeted to low (0.08–0.09%), medium (0.11–0.13%), and high (0.15–0.16%) blood alcohol concentrations (BACs) by using a method previously described. At lower BACs, most police officers were unable to identify whether or not targets had been drinking. Raters were “pretty sure” that targets in the 0.15–0.16% range had been drinking and “not sure” whether or not they should be served another drink or drive a car.

Conclusions: The ability of raters to reliably identify target drinkers who were too intoxicated to drive safely was not obtained until the BACs were relatively high. These results suggest that prevention measures must focus on improving behavioral observations made of potential drunk drivers. Implications for bartenders and social hosts are discussed.
Serotonin Transporter Promoter Polymorphism Genotype Is Associated With Behavioral Disinhibition and Negative Affect in Children of Alcoholics
Authors: Twitchell Geoffrey R. , Hanna Gregory L. , Cook Edwin H. , Stoltenberg Scott F. , Fitzgerald Hiram E. , Zucker Robert A.
Published: April 2006

Background : Serotonergic (5‐HT) dysfunction has been implicated in the etiology of both behavioral disinhibition (BD) and negative affect (NA). This work extends our previous finding of relationships between whole blood 5‐HT and both BD and NA in pubescent, but not prepubescent, children of alcoholics and continues examination of a hypothesized role of 5‐HT dysfunction in alcoholism risk. The long and short (L and S) variants of the 5‐HT transporter gene‐linked polymorphic region (5‐HTTLPR) are responsible for differing transcriptional efficiencies in 5‐HT uptake. Although associations have been found between the SS 5‐HTTLPR genotype and severe alcoholism and neuroticism, recent reports describe relationships between the LL genotype and both low level of response to alcohol and alcoholism diagnosis and a predominance of the LL genotype in early‐onset alcoholics.

Methods: This report is from an ongoing prospective study of the development of risk for alcoholism and other problematic outcomes in a sample of families classified by father's alcoholism subtype. This study examines relationships between 5‐HTTLPR genotype and both child BD (Child Behavior Checklist Aggressive Behavior) and NA (Child Behavior Checklist Anxious/Depressed) in offspring from 47 families.

Results: Results showed significantly higher levels of BD and NA in the 16 children with the LL genotype than the 46 SS or SL children.

Conclusions: Behaviors of undercontrol, which occur at increased rates in children of alcoholics, may be genetically influenced through the regulation of the 5‐HT transporter. Due to the small sample size and the preliminary nature of our findings, replication is necessary.
P3 Event‐Related Potential, Dopamine D2 Receptor A1 Allele, and Sensation‐Seeking in Adult Children of Alcoholics
Authors: Ratsma Joëlle E. , van der Stelt Odin , Schoffelmeer Anton N. M. , Westerveld Andries , Boudewijn Gunning W.
Published: April 2006

Background : Research has indicated a close relationship between the P3 event‐related potential and the dopamine D2 receptor A1 allele in individuals at high risk for alcoholism. Other research has suggested an association between the dopamine D2 receptor A1 allele and sensation‐seeking. In this study, we further examined the relationships between the P3, the A1 allele, and sensation‐seeking in a sample of nonalcoholic adult children of alcoholics.

Methods: Participants (n= 57; range, 19–30 years; 41 women), who performed a visual novelty oddball task to elicit the P3, were asked to fill in personality questionnaires, including Zuckerman's Sensation‐Seeking Scale, and were classified according to the presence of the dopamine D2 receptor A1 allele. The effects of sex, age, and socioeconomic status were assessed to determine whether these variables affected the relations between the P3, the A1 allele, and sensation‐seeking.

Results: A small P3 amplitude was associated with high sensation‐seeking, particularly with high disinhibition. The presence of the A1 allele was also associated with high disinhibition, but only in men. By contrast, P3 amplitudes and latencies were not associated with the presence of the A1 allele.

Conclusions: Although a small P3 amplitude, high sensation‐seeking, and the presence of the A1 allele were all associated with alcoholism risk, these findings indicate that these three characteristics together do not reflect a common risk factor in alcoholism.
Chronic Ethanol Enhances Adenosine Antiadrenergic Actions in the Isolated Rat Heart
Authors: Fenton Richard A. , Chung Eugene S.
Published: April 2006

Background : Chronic alcohol consumption elicits an increase in catecholamine release, which may be detrimental to heart function. Adenosine attenuates adrenergic stimulation via an adenosine receptor–mediated antiadrenergic action. This study investigated the effect of ethanol on adenosine antiadrenergic actions and adenosine release in the rat heart.

Methods: Rats were pair‐fed a liquid diet with or without ethanol for 4 weeks or 8 months. Hearts were isolated for determination of contractile function, and coronary effluents were collected for adenosine content. Dose‐response relationships for phenylisopropyladenosine (PIA) were determined for hearts adrenergically stimulated by isoproterenol. Experiments were also conducted with normal hearts with or without ethanol (25 mM) administered acutely. The effect of PIA on adenylyl cyclase activities of adrenergic‐stimulated crude membrane preparations obtained from alcoholic and nonalcoholic hearts was determined.

Results: Acute ethanol reduced basal adenosine release by 39%, but it did not significantly decrease adenosine release during adrenergic stimulation. In hearts chronically treated with ethanol for 4 weeks, adenosine release values before and during adrenergic stimulation were significantly reduced from control values. After 8 months of ethanol, adenosine release was similar with or without adrenergic stimulation. PIA 50% inhibiting concentration (IC50) values for contractile function were reduced from pair‐fed control values. Acute ethanol did not significantly change the PIA IC50 value. Chronic ethanol reduced the PIA IC50 for adenylyl cyclase by 96%.

Conclusions: Chronic ethanol treatment increases the antiadrenergic action of adenosine by mechanisms that seem independent of changes in adenosine concentration. Therefore, adenosine‐induced cardioprotection against increased catecholamine stimulation is enhanced by ethanol.
Relationship of Brain Ethanol Metabolism to the Hypnotic Effect of Ethanol. I: Studies in Outbred Animals
Authors: Zimatkin Sergey M. , Liopo Anton V. , Slychenkov V. S. , Deitrich Richard A.
Published: April 2006

Background : This study was designed to investigate the relationship between the ethanol‐oxidizing capacity of the brain, accumulation of acetaldehyde, and ethanol‐induced hypnosis in animals in vivo.

Methods: Randomly outbred albino rats were treated with ethanol, and the duration of ethanol‐induced loss of the righting response (sleep time) was measured. They were killed 2 weeks later (without further in vivo administration of ethanol), and brain homogenates were prepared to measure the accumulation of acetaldehyde from ethanol added in vitro. In a similar way, we determined the sleep time and, 5 days later, the rates of acetaldehyde accumulation in brains of heterogeneous mice.

Results: Significant correlations between the duration of ethanol‐induced sleep and acetaldehyde accumulation in vitro were found. The Km value of the process of acetaldehyde accumulation was lower in long‐sleeping, as compared with short‐sleeping, rats. A similar result was also obtained in genetically heterogeneous mice. Animals with a longer duration of ethanol‐induced sleep had a higher level of the accumulation of ethanol‐derived acetaldehyde in brain homogenates, as compared with the short‐sleeping mice. Rats and mice with the intermediate duration of ethanol‐induced sleep had an intermediate value of acetaldehyde accumulation in brain homogenates. There was no correlation between brain catalase activity and ethanol‐induced loss of the righting response in either the rats or the mice.

Conclusions: This study is a direct demonstration of the positive correlation between ethanol‐derived acetaldehyde accumulation in vitro in the brain and a central (behavioral) effect of alcohol in outbred rats and mice in vivo.
Effect of Naloxone on Appetitive and Consummatory Phases of Ethanol Self‐Administration
Authors: Sharpe Amanda L. , Samson Herman H.
Published: April 2006

Background : The opioid system has been implicated in ethanol self‐administration. Morphine, an opiate agonist, can sometimes increase the amount of ethanol consumed, and opiate antagonists such as naloxone and naltrexone decrease the amount of ethanol consumed in both animals and humans. The objective of this study was to examine the effect of naloxone on appetitive (or seeking) and consummatory behaviors by using an operant model developed to separate these two phases of self‐administration.

Methods: Intraperitoneal injections of naloxone (0.3–10 mg/kg) or vehicle were given before operant self‐administration sessions to assess the effect on lever pressing (appetitive behavior) and subsequent consumption. Effects were measured in two groups of rats: one self‐administered a 3% sucrose solution and the other a 10% ethanol solution.

Results: Naloxone dose‐dependently decreased ethanol and sucrose consumption by an earlier cessation of drinking in the session compared with vehicle injection days. There were some effects on appetitive responding after treatment with naloxone, but none was statistically significant.

Conclusions: Naloxone may decrease ethanol self‐administration by decreasing the postingestive or pharmacological effects of alcohol. This model provides a new method for examining the effects of potential pharmacotherapeutics on alcohol self‐administration behavior.
Inhibition of Insulin‐Like Growth Factor‐I Signaling by Ethanol in Neuronal Cells
Authors: Hallak Hazem , Seiler Andrea E. M. , Green Jamie S. , Henderson Aaron , Ross Brian N. , Rubin Raphael
Published: April 2006

Background : Ethanol inhibits insulin‐like growth factor‐I receptor (IGF‐IR) activation. However, the potency of ethanol for inhibition of the IGF‐IR and other receptor tyrosine kinases varies considerably among different cell types. We investigated the effect of ethanol on IGF‐I signaling in several neuronal cell types.

Methods: IGF‐I signaling was examined in SH‐SY5Y neuroblastoma cells, primary cultured rat cerebellar granule neurons, and rat NG‐108 neuroblastoma × glioma hybrids. The tyrosine phosphorylation of IGF‐IR, IRS‐2, Shc, and p42/p44 MAP kinase (MAPK), and the association of Grb‐2 with Shc, were examined by immunoprecipitations and Western blotting.

Results: IGF‐I–mediated tyrosine phosphorylation of MAPK was inhibited by ethanol in all cell lines. IGF‐IR autophosphorylation was markedly inhibited by ethanol in SH‐SY5Y cells, was only mildly inhibited in cerebellar granule neurons, and was unaffected in rat NG‐108 cells. In vitro tyrosine autophosphorylation of immunopurified IGF‐IR obtained from all cell lines was inhibited by ethanol. There was also differential ethanol sensitivity of IRS‐2 and Shc phosphorylation, and the association of Shc with IRS‐2, among the different cell types.

Conclusions: The findings demonstrate that IGF‐I–mediated MAPK activation is a sensitive target of ethanol in diverse neuronal cell types. The data are consistent with ethanol‐induced inhibition of IGF‐IR activity, although the extent of IGF‐IR tyrosine autophosphorylation per se is a poor marker of the inhibitory action of ethanol on this receptor. Furthermore, despite uniform inhibition of MAPK in the different neuronal cell types, tyrosine phosphorylation of proximal mediators of the IGF‐IR are differentially inhibited by ethanol.
Origins and Consequences of Age at First Drink. I. Associations With Substance‐Use Disorders, Disinhibitory Behavior and Psychopathology, and P3 Amplitude
Authors: McGue Matt , Iacono William G. , Legrand Lisa N. , Malone Steve , Elkins Irene
Published: April 2006

Background: Although an early age at first drink has been repeatedly associated with substantially elevated rates of alcoholism, the mechanisms underlying this association remain unclear. We investigated whether the association of age at first drink (AFD) with alcoholism was more consistent with the hypothesis that the former causes the latter or the hypothesis that both are manifestations of some common vulnerability.

Methods: We investigated whether substance use and mental health disorders, education, IQ, and personality were associated with AFD in a sample of 2670 adults; whether P3 amplitude was associated with AFD in a sample of 1127 17 year olds; and whether indicators of disinhibitory psychopathology assessed at age 11 predicted AFD by age 14 in a sample of 1343 adolescents.

Results: In adults, AFD was associated not only with alcohol dependence, but also with a broad array of indicators of disinhibitory behavior and psychopathology including nicotine dependence, illicit drug abuse and dependence, conduct disorder, antisocial personality disorder, underachievement in school, and the personality trait of constraint. In 17 year olds, AFD was also associated with reduced P3 amplitude, a well‐documented psychophysiological marker of alcoholism risk. Finally, in the early‐adolescence sample, measures of behavioral disinhibition, including oppositionality, hyperactivity/impulsivity, and inattentiveness assessed at age 11 predicted drinking onset by age 14.

Conclusions: Our findings indicated that AFD is not specifically associated with alcoholism but rather is correlated with a broad range of indicators of disinhibited behavior and psychopathology. Moreover, individuals who first drink at a relatively early age manifest elevated rates of disinhibitory behavior and psychopathology before they first try alcohol. Taken together, these findings suggest that the association of AFD with alcoholism reflects, at least in part, a common underlying vulnerability to disinhibitory behavior. Whether an early AFD directly influences risk of adult alcoholism remains unclear.