Showing papers in "Alcoholism: Clinical and Experimental Research in 1996"
TL;DR: Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.
Abstract: It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.
591 citations
TL;DR: The data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence, and they support the use of this paradigm for further investigations into the neuropharmacological mechanisms mediating reinforcement in dependent versus nondependent animals.
Abstract: Dependence is an important factor motivating continued alcohol use in human alcoholics. Development of a model of ethanol (EtOH) consumption in dependent animals would advance the understanding of reinforcement after chronic EtOH exposure and allow for the investigation of the neuropharmacological mechanisms mediating reinforcement in dependent versus nondependent animals. In the present study, rats were trained to lever press for 10% EtOH, surgically implanted with bilateral guide cannulae in the amygdala, and either made dependent on EtOH by exposure for 2 weeks to EtOH or exposed to air in identical vapor chambers. Upon removal, the rats were placed in operant boxes and allowed to respond on levers for 10% EtOH or water during a 12-hr period. Rats were removed briefly at approximately 6.5 hr for intra-amygdala injections of saline or the GABAA receptor agonist muscimol. After the test period, rats were returned to the vapor chambers for 4 days before retest. EtOH-dependent animals responded more for EtOH across the 12-hr test period than did air control nondependent rats; this difference became more pronounced with repeated test sessions. Intra-amygdala muscimol significantly decreased responding for EtOH in EtOH-dependent rats, but had no effect in nondependent controls. These data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence, and they support the use of this paradigm for further investigations into the neuropharmacology of EtOH dependence.
326 citations
TL;DR: Volumetric analyses demonstrated significant reductions in the cerebral vault, basal ganglia, and diencephalon in the children with fetal alcohol syndrome, compared with control children, which may relate to behavioral findings in both humans and animals exposed to alcohol prenatally.
Abstract: Magnetic resonance imaging was conducted on six children and adolescents with fetal alcohol syndrome and seven matched normal controls Detailed volumetric analyses demonstrated significant reductions in the cerebral vault, basal ganglia, and diencephalon in the children with fetal alcohol syndrome, compared with control children In addition, the volume of the cerebellar vault was smaller than controls in 4 of the 6 children with fetal alcohol syndrome, although the group difference did not reach significance When the basal ganglia were divided into the caudate and lenticular nuclei, both of these regions were significantly reduced in the children with fetal alcohol syndrome Finally, when the overall reduction in brain size was controlled, the proportional volume of the basal ganglia and, more specifically, the caudate nucleus was reduced in the children with fetal alcohol syndrome These results may relate to behavioral findings in both humans and animals exposed to alcohol prenatally
272 citations
TL;DR: The results of both studies indicate similar patterns of abnormal brain development in the anterior vermal region, with apparent sparing in the posterior vermal area, which suggests regionally specific Purkinje cell death may also occur in humans prenatally exposed to alcohol.
Abstract: Abnormalities of the cerebellar vermis have been well documented in animal models of fetal alcohol syndrome. At this point, it is not known if the same brain region is affected in humans prenatally exposed to alcohol. In this study, the area of the cerebellar vermis was measured from brain magnetic resonance images of 9 children and young adults with prenatal alcohol exposure and 24 control subjects in the same age range. Six of the exposed children met standard criteria for fetal alcohol syndrome. The remaining three subjects had significant histories of prenatal exposure to alcohol, but did not have enough of the classic facial features for the diagnosis. For each subject with a suitable midsagittal section, three vermal areas were circumscribed: anterior vermis (vermal lobules I-V), posterior vermis (vermal lobules VI and VII), and the remaining vermal area (including lobules VIII-X). Statistical analyses revealed that the anterior region of the vermis was significantly smaller in subjects with prenatal alcohol exposure, whereas the posterior region and the remaining vermal area did not differ between groups. Previous findings from an animal model of neonatal alcohol exposure have documented Purkinje cell loss in vermal lobules I-V and IX-X, with notable sparing in lobules VI-VII. Thus, the results of both studies indicate similar patterns of abnormal brain development in the anterior vermal region, with apparent sparing in the posterior vermal region. Our findings, for the first time, suggest that regionally specific Purkinje cell death may also occur in humans prenatally exposed to alcohol.
237 citations
TL;DR: Children with fetal alcohol syndrome were administered the California Verbal Learning Test-Children's Version, a word list learning task that assesses immediate and delayed recall and recognition memory and had difficulty learning and recalling the words after a delay period.
Abstract: Children with fetal alcohol syndrome (FAS) were administered the California Verbal Learning Test-Children's Version, a word list learning task that assesses immediate and delayed recall and recognition memory. When compared with matched control children, the children with FAS had difficulty learning and recalling the words after a delay period and tended to make an increased number of intrusion and perseverative errors. In addition, they had difficulty discriminating target words from distracter words and made more false-positive errors on recognition testing. Some of these deficits persisted even when mental age was controlled. The results suggest that children with FAS have profound verbal learning and memory deficits, and that some of these deficits cannot be accounted for even when mental age is considered. Furthermore, the results are consistent with deficits in encoding verbal information and impairment in response inhibition capabilities.
235 citations
TL;DR: Peri-adolescent rats are less sensitive to the sedative effects of ethanol as they recovered their righting reflex earlier and at significantly higher SECs than adult rats.
Abstract: Alcohol use in children and adolescents is widespread. However, very little is known about the effects of alcohol exposure during this period of postnatal development. The goal of the present study was to compare the relative sensitivity to the sedative effects of alcohol in periadolescent and adult rats. After treatment with either 4 or 5 glkg ethanol, both 20- and 30-day-old rats regained their righting reflex significantly earlier than 80-day old rats. In 30-day-old rats, serum ethanol concentrations (SECs) were significantly greater at the time of the recovety of the righting reflex than 80-day-old rats. Developmental differences in the effects of ethanol on locomotor activity were also observed. In 60-day-old rats, 2.5 glkg ethanol generally decreased locomotor activity. Ethanol did not significantly alter locomotor activity in 20- and 30-day-old rats. Finally, there were sig nificant developmental differences in the pharmacokinetics of ethanol with a significant delay in the time to peak SECs in 80-day-old rats relative to 20- and 30-day-old rats. These findings indicate that periadolescent rats are less sensitive to the sedative effects of ethanol as they recovered their righting reflex earlier and at significantly higher SECs than adult rats.
234 citations
TL;DR: It is found that ethanol-induced elevation in Mø IL-10 levels contributes to the decreased Mø TNF alpha production to bacterial challenge in ethanol-exposed Mø, suggesting that ethanol likely has an IL- 10 independent, direct effect on early signaling events of TNFalpha induction.
Abstract: We and others have previously shown that even acute ethanol exposure has the capacity to modulate immune functions, particularly monocyte functions. Herein, we tested the hypothesis that acute ethanol treatment inhibits inflammatory, while increasing inhibitory cytokine production in human blood monocytes that, in turn, could contribute to the overall immune abnormalities seen after alcohol use. Our data show that in vitro treatment of blood monocytes with a physiologically relevant dose of alcohol (25 mM) results in significantly decreased induction of tumor necrosis factor-alpha (TNF alpha) and interleukin (IL)-1 beta by bacterial stimulation of either Gram-positive [staphylococcal enterotoxin B (SEB), 1 microgram/ml of SEB] or Gram-negative [lipopolysaccharide (LPS), 1 microgram/ml of LPS] origin both at the protein and mRNA levels. In contrast, acute ethanol treatment induces monocyte production of mediators with immunoinhibitory potential, including transforming growth factor-beta and IL-10. We further show that ethanol not only induces monocyte/macrophage (Mo) IL-10 and transforming growth factor-beta, but even augments bacterial (both LPS and SEB) stimulation-induced production of both of these cytokines. IL-10 is a potent inhibitor of Mo TNF alpha production. We found that ethanol-induced elevation in Mo IL-10 levels contributes to the decreased Mo TNF alpha production to bacterial challenge in ethanol-exposed Mo. However, mRNA levels for TNF alpha are downregulated as early as 1.5 hr after ethanol treatment, suggesting that ethanol likely has an IL-10 independent, direct effect on early signaling events of TNF alpha induction.
213 citations
TL;DR: The data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.
Abstract: A brain image averaging technique was applied to three-dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel-by-pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age-matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional-deficient condition, Marchiafava-Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.
200 citations
TL;DR: It is recommended that, in the absence of a comorbid mood or anxiety disorder, fluoxetine not be used to maintain abstinence or reduce drinking in high-risk/severity alcoholics.
Abstract: OBJECTIVE The aim of this study was to test the hypothesis that, because of abnormalities in serotonergic neurotransmission that may underlie craving and impulsive behavior, fluoxetine treatment differentially affects drinking among type B alcoholics, who are characterized by high levels of both premorbid vulnerability and alcohol-related problems METHODS Using a k-means clustering procedure, alcohol-dependent subjects from a placebo-controlled trial of fluoxetine were grouped into low-risk/severity (type A: n = 60) and high-risk/ severity (type B: n = 35) groups Multivariate analysis of covariance (with pretreatment measures as covariates) evaluated the effects of Alcoholic Subtype, Medication Group, Treatment Completion, and their interactions on measures of drinking, both during the 12-week treatment period and a 6-month follow-up period RESULTS Although there were no main effects of Alcoholic Subtype or Medication Group, subjects who completed the treatment trial showed significantly better drinking-related outcomes There was also an interaction of Alcoholic Subtype by Medication Group during treatment Among type B subjects, fluoxetine treatment resulted in poorer drinking-related outcomes than placebo treatment Among type A subjects, there was no effect of Medication Group This interactive effect did not persist during the 6-month follow-up period CONCLUSIONS Alcoholic subtypes identified by cluster analysis seem to be differentially responsive to the effects of fluoxetine treatment on drinking-related outcomes Serotonergic abnormalities previously identified among a subgroup of alcoholics who are also characterized by impulsivity and severity of alcohol dependence may help to explain the differential medication effect Based on these findings, it is recommended that, in the absence of a comorbid mood or anxiety disorder, fluoxetine not be used to maintain abstinence or reduce drinking in high-risk/severity alcoholics
195 citations
TL;DR: Alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.
Abstract: We attempted to identify distinctive subtypes of alcoholics using latent class analysis with data from 2551 relatives of alcoholic pro-bands, all participants in the Collaborative Study of the Genetics of Alcoholism. Latent class analysis is a multivariate technique using cross-classified data to identify unobserved (“latent”) classes that explain the relationships among observed variables. Data on 37 lifetime symptoms of alcohol dependence from 1360 female and 1191 male relatives were analyzed, with a 4 class solution selected as the best fitting among the 2 through 6 class solutions that were examined. We observed the following classes: class 1, nonproblem drinkers (39.6% male, 50% female); class 2, mild alcoholics (persistent desire to stop, tolerance, and blackouts) (31.8% male, 28.7% female); class 3, moderate alcoholics (social, health, and emotional problems) (18.9% male, 14.6% female); and class 4, severely alfected alcoholics (withdrawal, inability to stop drinking, craving, health, and emotional problems) (9.7% male, 6.7% female). There was little evidence for the construct of alcohol abuse; endorsement probabilities for abuse symptoms (e.g., arrests and DWIs) were very low for all classes, whereas hazardous use was common among men in class 1. In addition to those in class 3 and class 4, a majority of men in class 2 qualified for DSM-Ill-R alcohol dependence, suggesting a bimodal distribution of drinkers and alcoholics, with little nondependent problem drinking among men in this high-risk sample. We conclude that, in this sample, alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.
193 citations
TL;DR: Findings from the study are generally consistent with predictions from Cloninger's type II model of excessive alcohol consumption in men with low CSF 5-HIAA, who also exhibit impaired impulse control and violent and antisocial behaviors.
Abstract: Developmental, biochemical, and behavioral concomitants of excessive alcohol consumption were investigated using a nonhuman primate model. The variables of interest were: (1) interindividual stability of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) from infancy to adulthood, (2) effect of parental deprivation early in life on adult CSF 5-HIAA concentrations; (3) correlations between CSF 5-HIAA and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations and alcohol consumption; and (4) correlation between the frequency of competent social behaviors and alcohol consumption. Twenty-nine rhesus macaques were reared for their first 6 months either with their mothers or without adults in peer-only conditions. At 6 and 50 months of age, each subject underwent a series of four, 4-day social separations. Cisternal CSF was sampled before and during the first and last separations; concomitantly, observational data were collected on social dominance behavior in the home-cage. When they reached 50 months of age, the monkeys were provided free access to a palatable alcohol solution daily for 1-hr periods before, during, and after the social separations. Before and after the 50-month separations, data were collected on all types of social behavior in the home-cage. Results showed that peer-reared subjects consumed more alcohol than mother-reared subjects during baseline conditions. Mother-reared subjects, however, increased their rates of consumption to equal peer-reared subjects' rates of consumption during the conditions of a social separation stressor. Peer-reared subjects also exhibited lower CSF 5-HIAA concentrations in infancy and adulthood than their mother-reared counterparts. With rearing condition held constant, interindividual differences in CSF 5-HIAA, MHPG, and homovanillic acid were stable from infancy to adulthood, and high rates of alcohol were consumed by the young adult monkeys with low CSF 5-HIAA and MHPG concentrations, particularly when the CSF was obtained during the social separations. High rates of alcohol consumption were also observed in subjects with infrequent social interactions and less competent social behaviors. In contrast to the human data, we found no gender differences in rates of alcohol consumption, nor in the correlations between alcohol consumption and the other variables. With some exceptions, findings from the study are generally consistent with predictions from Cloninger's type II model of excessive alcohol consumption in men with low CSF 5-HIAA, who also exhibit impaired impulse control and violent and antisocial behaviors.
TL;DR: The activity of the HPA axis is influenced by exposure to EtOH during embryonic development, with mature offspring showing hyporesponsiveness to many stimuli, and altered responses appear to be caused in part by changes in the synthesis/release CRF, possibly under the influence of nitric oxide.
Abstract: This review discusses some of the mechanisms through which alcohol (EtOH) alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis. In adult rats, acute EtOH treatment increases plasma ACTH and corticosteroids levels primarily by stimulating the release of corticotropin-releasing factor (CRF) and possibly vasopressin (VP) from nerve terminals in the median eminence. Increased CRF gene transcription in the hypothalamus may also be important. The HPA axis remains activated during chronic EtOH exposure, although habituation may take place. Changes in the responsiveness of hypothalamic neurons, a phenomenon itself dependent in part on a number of intermediate secretagogues, as well as decreased pituitary responsiveness to VP, all play a role. Finally, the activity of the HPA axis is influenced by exposure to EtOH during embryonic development, with mature offspring showing hyporesponsiveness to many stimuli. These altered responses appear to be caused in part by changes in the synthesis/release CRF, possibly under the influence of nitric oxide. CRF, VP, ACTH, and corticosteroids are important regulators of the immune system, behavior, metabolic pathways, and reproductive parameters. Alcohol therefore may influence such functions through the pathological secretion of these hormones. A better understanding of the mechanisms through which the drug alters their release thus may permit the development of therapies designed to alleviate some of the consequences of alcoholism.
TL;DR: The relationship was partially reduced by the addition of IQ to the model, but prenatal alcohol exposure still predicted significant deficits in achievement, even after controlling for IQ.
Abstract: This is a report on the effects of prenatal alcohol exposure on the academic achievement of children at 6 years of age. In this longitudinal study, women were interviewed at the end of each trimester of pregnancy, at delivery, and at 8, 18, 36, and 72 months postpartum. The women were of lower socioeconomic status, high school-educated, and moderate users of alcohol. The offspring received age-appropriate physical and developmental assessments at each follow-up. Linear regression and nonlinear curve fitting were used to investigate the nature and shape of the relationship between prenatal alcohol exposure and achievement. In addition, the role of child IQ in this relationship was explored. Alcohol exposure during the second trimester predicted deficits in each of the three subtests of the Wide Range Achievement Test-Revised (WRAT-R): reading, spelling, and arithmetic. The relationship was partially reduced by the addition of IQ to the model, but prenatal alcohol exposure still predicted significant deficits in achievement, even after controlling for IQ. Tests for the shape of the relationship demonstrated that the effect of prenatal exposure on the arithmetic subtest of the WRAT-R was a linear or dose-response relationship. By contrast, the relationships between prenatal alcohol exposure and performance on the spelling and reading subtests of the WRAT-R were better modeled as threshold effects. The thresholds for both were approximately 1 drink/day in the second trimester.
TL;DR: The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis, and the model should be useful for studying mechanisms of ethanol- induced selective cortical and olfactory brain damage.
Abstract: Severe, repetitive ("binge") ethanol intoxication in adult rats (intragastric delivery 3 times daily for 4 days in a modification of the Majchrowicz method) precipitates neuronal degeneration in selected cerebral cortical regions involved in memory and olfaction, confirming the results of Switzer and colleagues (Anat. Rec. 202: 186a, 1982). Neuronal damage was visualized with the de Olmos cupric silver technique for degenerating neurons and processes (argyrophilia), and was quantitated by total counts and densities of argyrophilic cells/fields. The specificity of the degeneration provides a neuropathological basis for the olfactory memory deficits in chronic alcoholics. In highly intoxicated rats, argyrophilia was most extensive among hippocampal dentate gyrus granule cells, pyramidal neurons in layer 3 of the entorhinal cortex, and olfactory nerve terminals in the olfactory bulb. Degenerating pyramidal neurons were also consistently seen in the insular cortex and olfactory cortical regions, such as the piriform and perirhinal cortices. There were few argyrophilic neurons in the CA regions of the hippocampus and none in the cerebellum--regions generally shown to have cell loss in long-term ethanol feeding models--but degenerating mossy fibers in the CA2 region were observed. Degeneration was maximal before the peak period of abstinence symptoms in this model, because argyrophilic densities were no greater 36 hr, compared with 8 hr after the last ethanol dose. High blood ethanol levels were required, because argyrophilia, absent from isocaloric controls, also was only evident in ethanol-intoxicated rats with mean blood ethanol levels for days 2 to 4 above 300 mg/dl; however, it increased substantially between 350 and 550 mg/dl. The resemblance of the argyrophilic distribution to the regional neuropathology that occurs in experimental seizures indicates that the ethanol-induced degeneration may have an excitotoxic basis. Progressive reductions in the seizure threshold (e.g., kindling phenomena that have been documented during binge ethanol intoxication) might be associated with excitotoxic hyperactivity during the repetitive nadirs between high blood and brain ethanol peaks. However, direct toxic actions of ethanol or its metabolites could also be involved. Overall, the model should be useful for studying mechanisms of ethanol-induced selective cortical and olfactory brain damage.
TL;DR: Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higheralcohol consumption, such as alcoholics.
Abstract: The effects of the genotype of alcohol dehydrogenase-2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.
TL;DR: Medical records of the 15,924 twin-pairs in the National Academy of Sciences-National Research Council (NAS-NRC) twin registry were collected for an additional 16 years through 1994 when the surviving twins were aged 67 to 77 years, and concordance rates remained similar to those reported 16 years earlier.
Abstract: Medical records of the 15,924 twin-pairs in the National Academy of Sciences-National Research Council (NAS-NRC) twin registry were collected for an additional 16 years through 1994 when the surviving twins were aged 67 to 77 years. Compared with earlier analyses (Hrubec, Z., and Omenn, G. S., Alcohol. Clin. Exp. Res., 5:207-215, 1981), when subjects were aged 51 to 61, there were 23% more diagnoses of alcoholism (34.4 per 1,000 prevalence), 32% more diagnoses of alcoholic psychosis (5.4 per l,000), and 25% more twins with liver cirrhosis (17.7 per 1,000). Overall, 5.3% of the cohort had at least one of the diagnoses related to alcoholism. Probandwise concordance rates (%) were: alcoholism—26.7 monozygotic (MZ), 12.2 dizygotic (DZ) (p < 0.0001); alcoholic psychosis—17.3 MZ, 4.8 DZ (p < 0.05); and cirrhosis—16.9 MZ, 5.3 DZ (p < 0.001). Concordance for any diagnosis related to alcoholism was 30.2 MZ, 13.9 DZ (p < 0.000l). Maximum-likelihood modeling indicated that ∼50% of the overall variance was due to additive genetic effects; in all diagnosis categories, a totally environmental model gave a significantly poorer fit to the data. Bivariate and trivariate genetic analyses indicated most of the genetic liability for the organ-specific endpoints of psychosis and cirrhosis was due to the shared genetic liability for alcoholism. Once the shared variance with alcoholism was considered, there was no further shared genetic liability for psychosis and cirrhosis. Our results confirm Hrubec and Omenn's conclusion that there was significantly greater concordance in MZ twins-pairs for alcoholic psychosis and cirrhosis in the NAS-NRC twins, and concordance rates remained similar to those reported 16 years earlier. In contrast, we found most of the genetic liability to organ-specific complications of alcoholism was shared with the genetic liability for alcoholism per se; only a small portion of the genetic variance of the individual complications was independent of the genetic predisposition for alcoholism.
TL;DR: Insight is provided into sex differences in the development of voluntary drinking behavior and responses of drinking behavior to the early stress of pair-feeding in Sprague-Dawley rats.
Abstract: Young male and female Sprague-Dawley rats (30 days old) were assigned randomly to three treatment groups: (1) alcohol treatment--received beer with 5% ethanol added, food, and water ad libitum; (2) pair-fed treatment--received nonalcoholic beer plus sucrose and food to match intake by the alcohol-treated animals; and (3) control treatment--received food and water ad libitum. Animals were tested for alcohol preference for 24 hr and then received their assigned treatments for a period of 30 days, followed by a period of abstinence before alcohol preference testing again at 74 days of age. Males given free access to beer and water did not drink large quantities of beer. Females given free access to beer and water drank a lot of beer on the first day, but decreased intake until approximately 52 days of age. A developmental change in young female rats at approximately 52 days of age resulted in increased voluntary ethanol intake, possibly caused by hormonal changes associated with the establishment of estrous cycles. When the animals were tested for alcohol preference at 74 days of age after a period of abstinence, males and females in the pair-fed group had greater alcohol preference than animals in the other groups. Females in the pair-fed group had greater alcohol intake based on body weight than males in the pair-fed group and males and females in all other groups. These results provide insight into sex differences in the development of voluntary drinking behavior and responses of drinking behavior to the early stress of pair-feeding.
TL;DR: Treatment studies may not be generalizable to alcoholics who do not seek treatment, and treatment history modified the associations between past-year status and race, marital and educational status, number of past alcohol problems, and rapidity of onset of dependence and age at onset.
Abstract: Past-year status was investigated in a sample of 4,585 adults with prior DSM-IV alcohol dependence. Those who had and had not received treatment for alcohol problems were compared in terms of past-year status and its correlates, to see if the experience of treatment samples would be reflective of the course of alcoholism in the general population. In the past year, 27.8% of the total sample met the criteria for alcohol abuse or dependence, 22.3% were abstinent, and 49.9% were drinkers who did not satisfy the criteria for either abuse or dependence. Persons who had been treated for alcohol problems were about twice as likely to be abstainers as those who had not been treated (38.8% vs. 16.4%), but only about half as likely to fall into the past-year category of drinking without abuse or dependence (28.0% vs. 57.8%). These differentials were of constant magnitude, regardless of the interval since the onset of dependence. For the sample as a whole, persons who had received treatment were slightly more likely than their untreated counterparts to have had alcohol abuse or dependence in the past year (33.2% vs. 25.8%), and this differential increased with the interval since the onset of dependence. The odds of both past-year abstinence and drinking without abuse or dependence were decreased by male gender, Black race, rapidity of the onset of dependence and ethanol intake per drinking day, and were increased by ever having been married and by later ages at onset of dependence. The odds of drinking without abuse or dependence relative to abstinence were increased by college attendance and reduced by the number of dependence symptoms, and having been a daily drinker was associated with increased odds of past-year abstinence. Treatment history modified the associations between past-year status and race, marital and educational status, number of past alcohol problems, and rapidity of onset of dependence and age at onset. These results suggest that treatment studies may not be generalizable to alcoholics who do not seek treatment.
TL;DR: Data from mice of the C57BL/6ByJ (B6) and 129/J (129) strains were consistent with the hypothesis that the higher ethanol intake by B6 mice depends, in part, on higher hedonic attractiveness of its sweet taste component.
Abstract: Mice of the C57BL/6ByJ (B6) and 129/J (129) strains were offered different concentrations of taste solutions in 48-hr, two-bottle choice tests. In comparison with the 129 strain, the B6 strain had higher preferences for ethanol, sucrose, and citric acid. They had lower preferences for NaCl and similar preferences for capsaicin and quinine hydrochloride. These data are consistent with the hypothesis that the higher ethanol intake by B6 mice depends, in part, on higher hedonic attractiveness of its sweet taste component.
TL;DR: Administration of EtOH to B6C3F1 mice by gavage produces behavioral changes, changes in blood EtOH levels, and probably glucocorticoid levels representative of at least some human binge drinkers.
Abstract: This study describes the development and characterization of a binge drinking model in which a single dose of ethanol (EtOH) is administered by gavage to B6C3F1 mice. Blood EtOH levels were monitored over time after administration of EtOH at doses of 3.0-7.0 g/kg. Peak levels were in the range of 0.2-0.5%, and clearance was complete within 2-12 hr. Substantial increases in blood corticosterone levels were noted. Behavioral changes in EtOH-treated mice aged 8 weeks ranged from no effect (3-4 g/kg) to severe ataxia (6-7 g/kg). In mice aged 16 weeks, a dosage of 7 g/kg caused less of the righting reflex in some animals and severe ataxia in most of the others. Clinical chemistry results did not indicate biologically important changes in general physiological/homeostatic systems in EtOH-treated mice, but there were indications of minor liver damage at the 7 g/kg dosage. Thus, administration of EtOH to B6C3F1 mice by gavage produces behavioral changes, changes in blood EtOH levels, and probably glucocorticoid levels representative of at least some human binge drinkers. The model was used to evaluate the effects of binge drinking on antibody responses, and the results indicate the model will be useful for such studies.
TL;DR: Co-treatment of the ethanol-exposed NCCs with free radical scavengers including 300 units/ml of superoxide dismutase, catalase, or alpha-tocopherol significantly improved NCC viability and suggest that free radicals play a significant role in ethanol-induced NCC death.
Abstract: Associations between ethanol-induced cranial neural crest cell (NCC) damage in mammalian embryos and subsequent malformations as observed in human fetal alcohol syndrome have previously been illustrated. The vulnerability of NCCs to this teratogen may result, at least in part, from their sensitivity to free radical damage. To examine relationships between free radical generation and NCC cytotoxicity, primary culture of mouse NCCs was used. NCC viability was determined in both dose- and time-response studies involving ethanol exposure. After 48 hr of culture, cell viability was significantly diminished at all doses tested (i.e., 50, 100, 150, and 200 mM ethanol). At 100 mM ethanol (a dosage that is teratogenic in vivo and in whole embryo culture), cell viability decreased to approximately 50% of control values over the first 12 hr of culture, and decreased further, to approximately 20% by 48 hr. Using nitroblue tetrazolium as a probe, it was observed that exposure of NCCs to ethanol stimulated the production of superoxide anion radicals. Co-treatment of the ethanol-exposed NCCs with free radical scavengers including 300 units/ml of superoxide dismutase, catalase (500 units/ml), or alpha-tocopherol (300 microM) significantly improved NCC viability. These results suggest that the ethanol-induced NCC injury is mediated, at least in part, through the generation of free radicals. To test this hypothesis further, NCCs were exposed in culture to xanthine/xanthine oxidase. Exogenous free radicals generated by the xanthine/xanthine oxidase system resulted in reduced NCC viability, the severity of which increased in a time and enzyme concentration-related manner. Superoxide dismutase (300 units/ml) and catalase (500 units/ml) significantly reduced the effects of the xanthine/xanthine oxidase-generated free radicals on NCC viability. The similarity between the susceptibility of NCCs to ethanol and their susceptibility to exogenous free radicals in concert with the free radical scavenger-mediated amelioration of ethanol and exogenous free radical-induced NCC death strongly suggest that free radicals play a significant role in ethanol-induced NCC death.
TL;DR: It is concluded that the peer-rearing paradigm aggravates the untoward social consequences associated with low CSF 5-HIAA concentrations over and beyond reducing CSF5-HiaA concentrations, suggesting that early experiences may contribute to CNS serotonin changes that increase the disposition to type II-related behaviors.
Abstract: The purpose of this study was to develop an animal model for behavioral features of type II, early-onset alcohol abuse. To perform this research, cerebrospinal fluid (CSF) monoamine metabolite concentrations and home-cage social behaviors of 29 rhesus macaque subjects were examined in a 4-year longitudinal study. Half of the monkeys were reared for their first 6 months with their mothers, and the other half were reared without adults, instead with access only to monkeys of similar age. When the subjects were 6 months old, and again when they were 50 months old, they underwent a series of four, 4-day social separations. We obtained cisternal CSF before and during the first and last separation of each series to quantify 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylgycol (MHPG), and homovanillic acid concentrations. After the 6-month separations, subjects were placed into social groups, and social dominance rankings were assessed. Before and after the 50-month separations, social dominance rankings were evaluated again, and home-cage aggression and social behavior data were collected. Over the 3 1/2 years between CSF samplings, records were maintained of subjects' removal from their social groups for excessive aggression or treatment for wounding. Our results showed that among infants, reduced CSF 5-HIAA was correlated with low social dominance. As young adults, subjects from both rearing groups with low CSF 5-HIAA and MHPG concentrations exhibited reduced rates of social interaction and low social dominance rankings. In addition, peer-reared subjects with low CSF 5-HIAA concentrations exhibited inept social behaviors, and were frequently removed from their social groups for excessive aggression and deviant social behaviors. From these results, we conclude that the peer-rearing paradigm aggravates the untoward social consequences associated with low CSF 5-HIAA concentrations over and beyond reducing CSF 5-HIAA concentrations, suggesting that early experiences may contribute to CNS serotonin changes that increase the disposition to type II-related behaviors. Language: en
TL;DR: Data indicate that asking patients about recent trauma is efficient and is well accepted as the first screening instrument in the identification of the problem drinker.
Abstract: Present methods to screen for alcohol abuse are generally obtrusive and result in referral to services that deal mainly with alcoholics. These factors deter physicians from identifying alcohol abuse patients at an early stage. In the present study, 81% of all primary care physicians of a single city evaluated (i) the efficiency and the acceptability of a nonobtrusive screening method for the identification of problem drinkers and (ii) the effectiveness of brief cognitive behavioral counseling given by a nurse in a lifestyle context. Patients (n = 15,686) attending the private practices of 42 primary–care physicians were asked four alcohol–neutral trauma questions in the reception area. Physicians asked about alcohol use and alcohol-related problems only to patients with previous trauma. Problem drinkers by defined criteria were offered an appointment with a nurse who, by random assignment, gave either 3-hr of cognitive behavioral counseling over 1 year or simply advised patients to reduce their alcohol intake. The screening method identified 62–85% of expected number of problem drinkers in this population. Following the application of exclusion criteria, 105 problem drinkers were entered in the intervention part of the study. After 1 year, patients who received counseling showed significant reductions in reported alcohol consumption (-70%; p < 0.001), psychosocial problems (-85%; p < 0.001) and serum gamma glutamyl transferase (-32%h to -58%; p < 0.02). Physician visits were reduced (-34%; p < 0.02) following counseling. Patients receiving only advice showed neither reductions in psycho-social problems nor in serum gamma glutamyl transferase or physician visits, but reported a 46% reduction (p < 0.01) in alcohol consumption. Data indicate that asking patients about recent trauma is efficient and is well accepted as the first screening instrument in the identification of the problem drinker. Cost of screening per patient is under one dollar. Counseling of 3 hr given by a nurse is markedly superior (p < 0.05) to simple advice in reducing alcohol consumption, objective indicators of alcohol-related morbidity, and the frequency of physician visits.
TL;DR: The results provided evidence that, for heavy drinking subjects, the presentation of phrases describing positive drinking outcomes significantly primed, or facilitated, responses to the alcohol-related words.
Abstract: Seventy-one subjects with various levels of drinking experience completed a computerized semantic priming task. Prime phrases (describing positive outcomes of drinking alcohol or neutral phrases) were presented immediately before a target word (either alcohol-related or not). The results replicated earlier basic research examining the effects of semantically related primes on the processing of subsequent words. Furthermore, the results provided evidence that, for heavy drinking subjects, the presentation of phrases describing positive drinking outcomes significantly primed, or facilitated, responses to the alcohol-related words. These results are consistent with the view that for some individuals, thoughts about certain outcomes automatically prime, or make accessible, concepts related to alcohol use. An increase in the accessibility of these concepts has important implications for behavioral decisions about alcohol consumption.
TL;DR: The frequency and extent of polydrug use was associated with being older and having higher levels of behavioral undercontrol and negative emotionality, and the use of alcohol and other drugs in combination was reported by a greater percentage of subjects in the alcohol dependence and abuse groups compared with drinkers without an alcohol diagnosis.
Abstract: Alcohol and other substance use disorders are highly comorbid, but little is known about patterns of polydrug use in adolescents with different levels of alcohol involvement. This research examined patterns and correlates of polydrug use in 176 adolescent drinkers with DSM-IV alcohol dependence (n= 61), alcohol abuse (n= 57), and no alcohol diagnosis (n= 58). Alcohol and other Substance Use Disorders were assessed using a modified version of the Structured Clinical Interview for the DSM. Lifetime histories of alcohol use and other drug use were assessed using a structured interview. Subjects also completed a questionnaire measure of the frequency of use of specific alcohol-drug combinations. The total number of illicit drugs ever used was greater in the alcohol dependence (mean = 3.8, SD = 2.1) and abuse groups (mean = 3.0, SD = 2.1), compared with the no-alcohol diagnosis group (mean = 1.9, SD = 1.3). Consistent with previous findings, there was a consistent pattern in the age of onset of psychoactive substance use: alcohol, followed by marijuana, followed by other drugs. The recent use of alcohol and other drugs in combination was reported by a greater percentage of subjects in the alcohol dependence (69%) and abuse groups (72%), compared with drinkers without an alcohol diagnosis (45%). The most common alcohol-drug combination was alcohol with marijuana (58% of the total sample), followed by alcohol-hallucinogens (16%). The frequency and extent of polydrug use was associated with being older and having higher levels of behavioral undercontrol and negative emotionality. Adolescent polydrug use, particularly the use of alcohol and other drugs in combination, is an important area for research, treatment, and prevention.
TL;DR: Assessment of agreement between DSM-IV, DSM-III-R, and ICD-10 diagnoses of alcohol and drug use disorders using data from a large representative sample of the United States population concluded that agreement between the three diagnostic systems for dependence was good to excellent.
Abstract: This study assessed agreement between DSM-IV, DSM-III-R, and ICD-10 diagnoses of alcohol and drug use disorders using data from a large representative sample of the United States population. Agreement between the three diagnostic systems for dependence was good to excellent for past year, prior to the past year, and lifetime diagnoses, for both genders, each ethnic group, and younger and older respondents. Cross-system comparisons between DSM-IV and DSM-III-R abuse were good to excellent, but concordance was consistently poor when ICD-10 harmful use diagnoses were compared with DSM-IV and DSM-III-R abuse diagnoses. Implications of these results are discussed in terms of the degree to which future research findings could be integrated with one another and the results from earlier studies using older versions of the DSM, to advance scientific knowledge in the drug and alcohol fields.
TL;DR: Although ethanol had no apparent effect on the proliferation of stem cells, it did alter the proliferation in the VZ and SZ, which underlie the ethanol-induced changes in the number of cells in the adult.
Abstract: The present in vivo study tests the hypothesis that limited (4-day) exposure to ethanol differentially affects the proliferation of cortical precursors in the two cortical germinal zones [the ventricular zone (VZ) and the subventricular zone (SZ)] and their descendants in the mature brain. The offspring of pregnant rats fed a liquid diet containing 6.7% (v/v) ethanol when prosencephalic stem cells [gestation day (G) 6-69], VZ cells (G12-G15), and SZ cells were proliferating (G18- G21) throughout much of gestation (G6-G21). In addition, the offspring of rats pair-fed a liquid control diet or fed chow were examined. The pregnant dams were administered with bromodeoxyuridine (BrdU) on either G15 or G21. The ratio of the number of cells that incorporated BrdU to the total number (the labeling index) was determined 1-hr postinjection (i.e., on G15 or G21) or on postnatal day 60, Ethanol treatment between G6 and G21 reduced the ratio of cells labeled by an injection of BrdU on G15 in the fetus and in the adult, and increased the ratio of cells labeled on G21. Regardless of when the injection was placed, ethanol treatment between G6 and G9 had no effect upon the ratio of BrdU-labeled cells in the fetus or mature cortex. Exposure from G12 to G15 decreased the number of VZ cells in the fetus and the number of immunolabeled cells in the adult cortex labeled by an injection on G15. This exposure had no effect on the incorporation by SZ cells. In contrast, ethanol exposure from G18 to G21 increased the labeling indices for fetal SZ cells and for cells in the adult, but it had no effect on the ratio of labeled VZ cells. Although ethanol had no apparent effect on the proliferation of stem cells, it did alter the proliferation of cells in the VZ and SZ. These effects are time-dependent and underlie the ethanol-induced changes in the number of cells in the adult.
TL;DR: The results suggest that alcoholism is associated with mammillary body and cerebellar tissue volume loss but do not provide evidence that these markers distinguish accurately between amnesic and nonamnesic patients and suggest that visualizable mammillaryBody atrophy is not necessary for the development of amnesia in alcoholic patients.
Abstract: Mammillary body and cerebellar atrophy have been described as postmorten neuropathologic markers of Korsakoff's syndrome. This study examined whether shrinkage in the mammillary bodies and cerebellum is present consistently in amnesic chronic alcoholics during life and whether the degree of abnormality in these patients differs from that in nonamnesic alcoholic and healthy controls. The severity of shrinkage in the mammillary bodies, cerebellar hemispheres, and cerebellar vermis visualizable on MRI scans was rated on a three-point scale in 33 chronic nonamnesic alcoholics, 9 amnesic alcoholics, and 20 healthy controls. Although both alcoholic groups showed significant mammillary body and cerebellar shrinkage relative to controls, the two patient groups did not differ from each other. Furthermore, four of eight amnesic patients in our sample did not demonstrate clinically significant mammillary body atrophy. These results suggest that alcoholism is associated with mammillary body and cerebellar tissue volume loss but do not provide evidence that these markers distinguish accurately between amnesic and nonamnesic patients. In addition, they suggest that visualizable mammillary body atrophy is not necessary for the development of amnesia in alcoholic patients.
TL;DR: The data demonstrate that fetal E-exposed males and females both exhibit hormonal hyperresponsiveness and/or deficits in recovery after repeated exposures to restraint stress, but that the patterns of response may differ depending on the number and duration of restraint exposures, the time course measured, and whether the endpoint measured is corticosterone, ACTH, or beta-EPLIR.
Abstract: Previous studies provide evidence that fetal ethanol exposure induces hypothalamic-pituitary-adrenal (HPA) and pituitary beta-endorphin (beta-EP) hyperresponsiveness to acute stressors. The present study demonstrates significant effects of in utero ethanol exposure on the parallel response patterns of the HPA axis and the pituitary beta-EP system to repeated exposures to a stressor, restraint stress, and indicates sex differences in response. Together, data from the two experiments indicate that, after repeated restraint exposures, fetal ethanol-exposed (E) males and females both show significantly increased plasma levels of adrenocorticotropin (ACTH), and E males also show significantly increased plasma levels of beta-endorphin-like immunoreactivity (beta-EPLIR), compared with their respective pair-fed and control counterparts. Marginal increases in the corticosterone response of E males and the beta-EPLIR response of E females, compared with their controls, were also observed. In addition, delayed or deficient habituation to restraint stress was observed in the beta-EPLIR response of E males and the ACTH response of E females. These data demonstrate that fetal E-exposed males and females both exhibit hormonal hyperresponsiveness and/or deficits in recovery after repeated exposures to restraint stress, but that the patterns of response may differ depending on the number and duration of restraint exposures, the time course measured, and whether the endpoint measured is corticosterone, ACTH, or beta-EPLIR. In addition, the finding that E and pair-fed animals both differed from their respective controls in certain developmental and hormonal measures suggests that prenatal nutritional factors may play a role in mediating some of the changes that are observed.