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PubMed1993

Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism.

The alcohol-flush reaction occurs in Asians who inherit the mutant ALDH2*2 allele that produces an inactive aldehyde dehydrogenase enzyme. In these individuals, high blood acetaldehyde levels are believed to be the cause of the unpleasant symptoms that follow drinking. We measured the alcohol elimination rates and intensity of flushing in Chinese subjects in whom the alcohol dehydrogenase ADH2 and ALDH2 genotypes were determined. We also correlated ADH2, ADH3, and ALDH2 genotypes with drinking behavior in 100 Chinese men. We discovered that ADH2*2 and ADH3*1, alleles that encode the high activity forms of alcohol dehydrogenase, as well as the mutant ALDH2*2 allele were less frequent in alcoholics than in controls. The presence of ALDH2*2 was associated with slower alcohol metabolism and the most intense flushing. In those homozygous for ALDH2*1, the presence of two ADH2*2 alleles correlated with slightly faster alcohol metabolism and more intense flushing, although a great deal of variability in the latter was noted.

Alcohol Dehydrogenase↗
PubMed1995

Reduced visuospatial performance in children with the D2 dopamine receptor A1 allele.

Previous studies suggest a reduced dopaminergic function in subjects with the A1 (minor) allele of the D2 dopamine receptor (DRD2) gene. To explore influences on visuospatial ability as a function of the DRD2 gene, 182 alcohol- and other drug-naive sons (age 10-14) of active alcoholic, recovered alcoholic, and nonalcoholic fathers were administered a visuospatial task (Benton's Judgment of Line Orientation Test) which makes minimal motoric/verbal demands. Visuospatial scores were lower for boys with the A1 allele and for sons of active alcoholics. A1-allele boys made more errors than A2 boys on all 11 of the template lines, with the effect being largest for the rightmost presentations. In contrast, the effect of family history for alcoholism was strongest on both right and left midquadrant presentations. Moreover, separate analyses of the two types of errors produced allele but not family history of alcoholism effects when the two lines were misjudged as farther apart than they actually were and family history but not allele effects where the two lines were misjudged as closer together. These results suggest that polymorphism of the DRD2 gene and family history of alcoholism are dissociable determinants of visuospatial ability and that visuospatial defects previously observed in alcoholics may, in part, be antecedent to their drinking behavior.

Adolescent↗
PubMedDate not supplied

Application of DNA microarrays to study human alcoholism.

An emerging idea is that long-term alcohol abuse results in changes in gene expression in the brain and that these changes are responsible at least partly for alcohol tolerance, dependence and neurotoxicity. The overall goal of our research is to identify genes which are differentially expressed in the brains of well-characterized human alcoholics as compared with non-alcoholics. This should identify as-yet-unknown alcohol-responsive genes, and may well confirm changes in the expression of genes which have been delineated in animal models of alcohol abuse. Cases were carefully selected and samples pooled on the basis of relevant criteria; differential expression was monitored by microarray hybridization. The inherent diversity of human alcoholics can be exploited to identify genes associated with specific pathological processes, as well as to assess the effects of concomitant disease, severity of brain damage, drinking behavior, and factors such as gender and smoking history. Initial results show selective changes in gene expression in alcoholics; of particular importance is a coordinated reduction in genes coding for myelin components.

Alcohol-Related Disorders↗
PubMedDate not supplied

Screening elderly veterans for alcoholism.

OBJECTIVE: To determine the sensitivity and specificity of an alcoholism screening test not previously tested in the elderly. DESIGN: Cross-sectional study, face-to-face interviews. SETTING: Veterans Administration (VA) outpatient facility. PATIENTS/PARTICIPANTS: Men greater than or equal to 70 years old seeking care in a newly established VA outpatient facility were invited to participate in a health assessment program. Of 109 participants who enrolled, 96 completed both interviews. INTERVENTIONS: The screening test was administered by an internist as part of a medical history. The Michigan Alcoholism Screening Test (MAST), used as the "gold standard," was administered by a trained interviewer as part of a longer structured interview. MEASUREMENTS AND MAIN RESULTS: The screening test had a sensitivity of 0.52 and a specificity of 0.76 in this sample. CONCLUSIONS: The sensitivity and specificity of the screening test were lower in this sample in comparison with previously reported results in a younger population. Differences in the test performance may be related to differences in attitudes and drinking behaviors of elderly veterans when compared with those of younger men and women.

Age Factors↗
PubMed2001

Adverse effects of oral naltrexone: analysis of data from two clinical trials.

RATIONALE: Naltrexone treatment of alcohol dependence is associated with adverse events that may limit its effectiveness. Consequently, understanding the impact of adverse events on medication compliance and treatment retention may enhance naltrexone therapy of alcoholism. OBJECTIVES: To examine the relations among adverse events, drinking behavior, medication compliance and study retention in alcoholics receiving naltrexone for relapse prevention. METHODS: The current report is based on analysis of data from 92 subjects who participated in two previously published studies. Moderate or severe adverse effects were monitored weekly and categorized as either neuropsychiatric (NP) or gastrointestinal (GI). Medication compliance was determined by weekly urinary riboflavin testing. Study retention was determined by the proportion of study weeks completed by the subject. The causal relations among adverse events, medication compliance and study retention were analyzed separately for NP and GI adverse events using regression-based recursive path models. RESULTS: Both the NP and GI models fit the data well [NP model: chi 2(4) = 0.59, P = 0.96; GI model: chi 2(4) = 2.81, P = 0.59]. NP adverse events exerted little influence on medication compliance (beta = -0.17, P = 0.071), but directly decreased the length of study retention (beta = -0.35, P < 0.001). In contrast, there was a significant impact of GI adverse events on medication compliance (beta = -0.29, P = 0.002), but not directly on study retention (beta = -0.14, P = 0.081). CONCLUSION: Future studies aimed at enhancing the effectiveness of naltrexone should examine ways of reducing both NP and GI adverse events, in order to enhance both medication compliance and treatment retention.

Administration, Oral↗
PubMed2005

Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese.

The Japanese have a polymorphism in the alcohol dehydrogenase 2 gene (ADH2). The alleles of ADH2 (ADH2*1 and ADH2*2) encode more active and less active forms for ethanol metabolism, respectively. We examined whether liver damage and the insulin-glucose axis vary according to ADH2 genotype in the Japanese. The 2,232 subjects (1,126 men and 1,106 women) were recruited from a population-based prospective cohort study. Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, gamma-GTP, and prevalence of diabetes were compared among the ADH2 genotypes. The percentage of drinkers, alcohol consumption, AST, ALT, and gamma-GTP were higher in group ADH2*1/1 than in group ADH2*1/2 or ADH2*2/2 (all P < 0.05). Hence, ADH2*1/1 is associated with excess alcohol intake and liver disorders. However, the prevalence of diabetes did not differ among the three groups. For the glucose-insulin axis, we examined subjects who did not receive insulin therapy or oral anti-diabetes medication. While amounts of alcohol consumed and glucose levels were nearly the same between ADH*1/2 and ADH2*2/2, insulin concentrations were lower in ADH2*2/1 than in ADH2*2/2 (P < 0.05 in men). This finding suggests that the ADH2*1 allele is associated with a lower insulin concentration when alcohol intake is light or moderate. It also suggests that the genetic effect of ADH2*1 plays an important role in alcohol drinking behavior and in the occurrence of liver injury, but the effect is so mild that it does not influence the glucose-insulin axis or prevalence of diabetes.

Alcohol Dehydrogenase↗
PubMed2005

Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci.

After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.

Adolescent↗
PubMed1994

Coping with traumatic brain injury: representative case studies.

This case report compares the use of social supports and vulnerability to substance abuse for two rehabilitation clients after traumatic brain injury (TBI). Using a psychosocial assessment, the Motivational Structure Questionnaire, Adaptive Skills Battery, and Ways of Coping Checklist within a representative case method, we studied two individuals in depth to understand differences in postinjury drinking behaviors. We also examined differences in availability and use of social supports and how support was related to coping efforts. Finally, we illustrated goal-setting and the relationship between long-term planning and follow-through on goals. Social supports, adaptive problem-solving behaviors, and positive reappraisal of situations seem to be important elements in postinjury abstinence. Clinically, this research supports the need for fostering use of both social supports and substance use prevention and treatment services when working with both inpatient and outpatient TBI clients.

Adaptation, Psychological↗
PubMed1976

Effects of subfornical organ extracts of salt-water balance in the rat.

The subfornical organ (SFO) is regarded as a neurosecretory structure but no information is available on the nature or biological effects of the secretory products(s). Supernatants of water homogenates of rat SFO were lyophilized and reconsittuted in artificial cerebrospinal fluid (CSF). Intracerebroventricular (IVT), but not subcutaneous, administration of this material to rats produced diuresis, natriuresis and kaliuresis in the following 8 h daylight period. During the overnight cycle, consummatory behavior and excretion of sodium and potassium were reduced. Similar responses were obtained after IVT administration of cerebellar cortex (CB) or large amounts of plasma. SFO, CB and cerebral cortex (CC) were incubated in potassium-enriched CSF to enhance release of secretory products. Urine volume was increased 8 h after IVT injection of SFO media; in the overnight cycle, food consumption, absolute urinary sodium and potassium, and [Na+-a1 were reduced. These effects were not produced by IVT injection of CC or CB media, or equal amounts of plasma proteins. Additional experiments demonstrated that choroid plexi and SFO effects were similar and that the active SFO material was dialyzable and thermal stable. These data suggest that SFO contains a water-soluble substance which is released into a posassium-enriched medium. The material is heat stable, has a relatively low molecular weight, and alters salt-water balance after injection into ventricular cerebrospinal fluid.

Animals↗
PubMed1984

Fetal suprachiasmatic nucleus transplants: diurnal rhythm recovery of lesioned rats.

The diurnal rhythm organization of drinking behavior was determined prior to and after suprachiasmatic nucleus (SCN) lesions. Five weeks after SCN lesions which produced total loss of the diurnal rhythm, the anterior hypothalamus including the SCN of fetal rats was transplanted into the floor of the 3rd ventricle of the lesioned rats. Eight weeks after the graft, rats recovered their rhythm. The results show that grafts allow animals to recover lost functional properties due to lesions, and further support the notion that the SCN is a pacemaker for certain behaviors.

Animals↗
PubMed1990

Sensitivity to angiotensin II of neurons in the circumventricular organs of polydipsic inbred mice.

The polydipsic inbred mice, STR/N, are known to possess an extremely strong appetite for drinking but no abnormality in the vasopressin system and renal functions. In brain slice preparations the sensitivity of neurons in the anteroventral region of the third ventricle (AV3V) and the subfornical organ (SFO) to angiotensin II (ANG II) was investigated using extracellular recordings in the STR/N and its control, Swiss/Webster (S/W) mice. In the AV3V, less proportion of neurons (15 out of 168; 9%) of the STR/N than that in the S/W (49/206; 24%) was excited by ANG II added to the medium. In the SFO, a proportion of neurons excited by ANG II was again lower in the STR/N (27/104; 26%) than in the S/W mice (64/118; 54%). The threshold concentration of ANG II for excitation of the AV3V and SFO neurons was, however, similar for both strains, 10(-9) M or less. Only one neuron in the SFO of a S/W mouse was inhibited by ANG II application. The excitatory effect of ANG II on AV3V and SFO neurons of both strains of mice persisted under synaptic blockade and was reversibly antagonized by an ANG II antagonist, saralasin. Such differences in sensitivity to ANG II of neurons in the SFO and AV3V, the regions thought to be involved in drinking behavior, suggest the involvement, at least in part, of the central angiotensin system in the polydipsia of the STR/N mice.

Angiotensin II↗
PubMed1996

Involvement of the opioid system in the anxiolytic effect of diazepam in mice.

In the present study, the anticonflict effect of diazepam was significantly abolished by pretreatment with naloxone, beta-funaltrexamine or nor-binaltorphimine but not naltrindole, using a Vogel-type conflict paradigm in mice. However, naloxone alone had a significant proconflict effect, and beta-funaltrexamine alone tended to produce a proconflict effect. Spontaneous drinking behavior was not affected by treatment with diazepam and nor-binaltorphimine. In addition, nor-binaltorphimine had no effect on diazepam-induced motor incoordination, hypothermia or anticonvulsant action, respectively. Moreover, the stable dynorphin analog E2078 ([N-methyl-Tyr1, N-alpha-methyl-Arg7-D-Leu8]dynorphin A-(1-8) ethylamide) and the highly selective kappa-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide++ + methanesulfonate hydrochloride) produced a significant anticonflict effect, which was completely antagonized by pretreatment with nor-binaltorphimine. These findings suggested that the kappa-opioid system may play an important role in the anxiolytic effect of benzodiazepine and the regulation of anxiety.

Analgesics, Non-Narcotic↗
PubMed1983

Effects of opiate agonists and antagonists on fluid intake and saccharin choice in the rat.

Both naloxone (3 and 10 mg X kg-1) and naltrexone (1-10 mg X kg-1) abolished the preference for a highly palatable 0.05% sodium saccharin solution in rats that had been adapted to a 22 hr water-deprivation schedule. The effect occurred as a result of a selective decrease in the consumption of the saccharin solution, since the intake of water, which was concurrently available in the two-fluid choice test, remained unaffected. When a less preferred saccharin solution was used (0.01%), naltrexone exerted a similar suppressant effect on the sodium preference, whilst naloxone failed to produce significant effects on the intake of saccharin solution or water. The data for the opiate agonists were interpreted in terms of a drug-induced blockade of the natural reward of highly palatable fluids in thirsty rats. In the same choice test, morphine and a stabilised enkephalin analogue, with a selective agonist action at mu-opiate receptors (RX783030), failed to influence the preference for the palatable saccharin solutions. In water-deprived animals, at least, exogenous opiate agonists, active at mu-receptors, did not appear to influence the reward of the palatable solutions.

Animals↗