Postural sway in children from pedigrees exhibiting a high density of alcoholism.

A total of 98 children participated in a study of the neurobehavioral characteristics of individuals from pedigrees in which there was a high density of alcoholism. Two groups of children were evaluated (High and Low Risk) using a sensitive movement platform and a variety of methods to challenge the motor system. High-Risk children showed a greater decrement in postural steadiness when visual input was removed than did Low-Risk children. Additionally, the monopedal stances revealed hemispheric differences in postural sway as a function of risk status. The amount of sway exhibited was correlated with the latency of P300 recorded using a visual task. Both appear to be indicators of neuropathological changes. The present results suggest that postural sway may be a neurobehavioral marker for alcoholism risk.

Personality resemblance in relatives of male alcoholics: a comparison with families of male control cases.

The Multidimensional Personality Questionnaire (MPQ) was administered to members of nuclear families in which alcoholism was segregating and another set of nuclear families in which no psychiatric illness, including alcoholism, was present. Intraclass correlations were calculated for pairs of relatives from the alcoholic families and compared with those obtained for control families. For particular traits, the correlations obtained for pairs of relatives from both family types were larger than those previously reported for dizygotic twins. Particularly striking was the absence of positive correlations for siblings discordant for alcoholism as contrasted with individuals concordant for alcoholism. The results suggest that removing the discordant effects of psychopathology tends to increase the overall similarity between relatives. Finally, particular traits were found to be significantly correlated in both family types, suggesting that some personality characteristics may reflect greater genetic mediation, whereas others, not found in common across families, may reflect differences in familial environmental factors.

Absence of visual and auditory P300 reduction in nondepressed male and female alcoholics.

BACKGROUND: The P300 component of the event-related potential has been extensively studied as a possible neurobiological risk marker for the development of alcoholism. Although P300 amplitude reduction has frequently been documented in high-risk children, studies of adult alcoholics are inconsistent. METHODS: P300 amplitude from 121 adult alcoholics was compared to 68 controls utilizing event-related potential paradigms from the auditory and visual modalities. All participants were evaluated clinically with psychiatric interviews and administered the MMPI. RESULTS: Male alcoholics did not show a reduction in amplitude in either the auditory or visual modality. Female alcoholics showed reduced P300 amplitude, but only when a comorbid lifetime diagnosis of depression was present. Similar results were found using current depressed mood (Scale 2 from the MMPI). CONCLUSIONS: No differences in P300 amplitude were found between alcoholics and controls unless comorbid depression was present. Therefore, P300 amplitude reduction seen in children at high-risk for developing alcoholism seems to represent a neurodevelopmental delay that normalizes by adulthood.

Path analysis of P300 amplitude of individuals from families at high and low risk for developing alcoholism.

BACKGROUND: A substantial amount of evidence exists suggesting that P300 amplitude in childhood is a risk marker for later development of alcohol dependence. There is evidence that P300 amplitude is heritable. The goal of the present study was to determine if patterns of transmission differed in families who were either at high or low risk for developing alcohol dependence. METHODS: Auditory P300 was recorded from 536 individuals spanning three generations. The path analytic TAU model was used to investigate the familial transmission of P300 amplitude in the two independent samples of families. RESULTS: Transmission of P300 in high-risk families most likely followed a polygenic model of inheritance with significant parent-to-offspring transmission. Parent-to-offspring transmission was significantly greater in high-risk than low-risk families. Total phenotypic variance due to transmissible factors was greater in low-risk families than in high-risk families, however. A somewhat unexpected finding was the substantial correlation between mates for P300 amplitude in both high- and low-risk families. CONCLUSIONS: P300 is transmissible in families. Differences exist in the pattern of transmission for P300 in families at high and low risk for alcoholism.

Factors predicting the onset of adolescent drinking in families at high risk for developing alcoholism.

BACKGROUND: With a longitudinal prospective design, the purpose of this study was 1) to assess, with survival analysis, the age of onset of drinking in relation to family history of alcoholism; 2) to examine the importance of selected neurobiological and psychosocial risk factors in predicting the onset to drink; and 3) to determine if the age of onset of substance dependence problems differed by risk group status. METHODS: One hundred twenty-five children and adolescents were evaluated annually (N = 638 evaluations), providing up to seven annual waves of longitudinal data. Survival analyses were performed to determine the age of onset of regular drinking and the age of onset for substance abuse/dependence. The age of onset of regular drinking outcome was modeled using familial density of alcoholism and four factors, which included neurobiological indices of development (postural sway and P300), personality characteristics, academic achievement, self-esteem, and trait anxiety. RESULTS: High-risk children/adolescents showed a significantly earlier age of onset of drinking and an earlier age of onset for substance abuse problems. Familial density of alcoholism predicted an earlier onset of drinking, as did having deficits in reading achievement, reduced P300 (visual and auditory), and greater postural sway for age. Higher scores on the Extraversion scale of the Junior version of the Eysenck Personality Inventory also predicted an earlier onset of drinking. CONCLUSIONS: Familial density of alcoholism (number of alcoholic first- and second-degree relatives) is an important predictor of adolescent alcohol initiation. Evidence is presented suggesting that part of the familial/genetic variation in outcome may be due to neurobiological factors and temperament.

P300 amplitude decrements in children from families of alcoholic female probands.

A total of 70 age- and gender-matched children and their relatives who were from families that were either at high or low risk for developing alcoholism were studied and the children evaluated using event-related potential paradigms from both the auditory and visual modalities. The high-risk children were ascertained through families at exceptionally high risk for female alcoholism (half of all female first- and second-degree relatives were alcoholic), while low-risk control families had been selected for absence of alcoholism in first- and second-degree relatives. Results indicate that reduced amplitude of P300 and greater negativity of N250 characterize children from high-risk families when evaluated with an auditory task. The visual task discriminated high- and low-risk groups for male children only, consistent with earlier findings for high-risk families ascertained through a male alcoholic. Further, daughters of alcoholic mothers (biological father nonalcoholic) display significantly lower P300 than matched controls, indicating that transmission of alcoholism risk may be possible from mother to daughter without the necessity of paternal alcoholism.

Developmental changes in postural sway in children at high and low risk for developing alcohol-related disorders.

BACKGROUND: To utilize the power of latent growth analysis to evaluate changes in postural sway during development in children who are either at high or low risk for developing alcoholism. METHODS: A total of 629 assessments of postural sway have been performed in children and adolescents (n = 126) who were evaluated annually over a 7-year period. RESULTS: Latent curve models indicated that these children/adolescents show a linear decrease in sway with age. Moreover, significantly different rates of change in the amount of sway between high- and low-risk offspring were seen. With the exception of one of the four stances tested, high-risk boys consistently showed a slower rate of improvement with respect to the amount of sway exhibited compared to low-risk boys. In girls, similar rates of improvement with age were seen in high- and low-risk individuals, though in one stance the high-risk girls showed a deterioration (greater sway with increasing age). CONCLUSIONS: Previous reports of increased postural sway in high-risk offspring most likely reflect a developmental delay (high-risk children have greater sway than is appropriate for their age based on normative values by age).

Developmental delay in P300 production in children at high risk for developing alcohol-related disorders.

BACKGROUND: Reduction of P300 amplitude in children and adolescents at high risk for developing alcoholism has frequently been reported. It has been hypothesized that this reduction represents a developmental delay in reaching age-appropriate levels in P300 amplitude. Using latent growth analysis of longitudinal data obtained at yearly intervals, this study seeks to define normal growth, and determine if the pattern seen in high-risk children differs from that obtained in normal low-risk controls. METHODS: A total of 156 children from either high or low-risk families have been assessed multiple times (two-thirds more than 4 times) using both a clinical assessment (K-SADS) and ERP evaluation performed on the same day. A total of 635 separate assessments were available for modeling. RESULTS: Quadratic growth curves revealed a slower rate of change in P300 amplitude in high-risk than low-risk males. High-risk girls showed reduced visual P300 amplitude only when the presence of a K-SADS diagnosis was considered. No differences were seen for P300 latency. CONCLUSIONS: This study confirms the hypothesis that when reduction of P300 amplitude is seen in males at high risk for developing alcoholism, it is due to a developmental delay.

Right amygdala volume in adolescent and young adult offspring from families at high risk for developing alcoholism.

BACKGROUND: Neurobiological factors have been implicated in the increased susceptibility for developing alcohol dependence that offspring from alcoholic families exhibit. The P300 component of the event-related potential shows developmental changes during childhood and adolescence that appear to be related to risk status. The underlying structural changes that accompany these neurophysiological changes are not well understood. METHODS: Magnetic resonance imaging was used to measure cerebral, amygdala, and hippocampal volumes in 17 high-risk adolescent and young adult offspring from multiplex alcoholism families and 17 age-, gender-, and IQ-matched control subjects without a family history for alcoholism or other substance dependence. Twenty-two of the subjects are part of a longitudinal prospective study and have been followed an average of 7.3 years, making it possible to relate P300 developmental trajectories to structural volumes. RESULTS: High-risk adolescents and young adults showed reduced right amygdala volume in comparison with control subjects. Right amygdala volume was significantly correlated with visual P300 amplitude. CONCLUSIONS: Offspring from families having a high density of alcoholism differ in both neurophysiological and neuroanatomical characteristics that could not be explained by personal drinking history or particular childhood and adolescent psychopathology. Because the amygdala tends to increase in volume during childhood and adolescence, smaller volumes in high-risk children may indicate a developmental delay that parallels delays seen in visual P300 amplitude.

Genetic association between reduced P300 amplitude and the DRD2 dopamine receptor A1 allele in children at high risk for alcoholism.

BACKGROUND: There is evidence that both reduction in P300 amplitude and the presence of the A1 allele are risk markers for alcoholism. We hypothesized that demonstration of a relationship between the marker and the trait in young children who had not begun to drink regularly would provide evidence for dopaminergic mediation of the reduction in P300 often seen among high-risk children. A previous association between the A1 and the P300 amplitude in screened controls supports the hypothesis that this association occurs in the general population. METHODS: Children were assessed using both visual and auditory paradigms to elicit event-related potentials (ERPs). The P300 component of the ERP was investigated with respect to the genetic variation of the Taq1A D2 receptor in these children. RESULTS: Genetic association between a marker locus (Taq1 A RFLP near the D2 receptor locus) and the amplitude of P300 was found to be present in 58 high-risk children and their relatives (a total of 100 high-risk individuals). CONCLUSIONS: A higher proportion of children from alcoholic families may exhibit lower P300 because more of these children carry the A1 allele than is seen in the normal population.

Computerized Transaxial Tomographic and Neuropsychological Evaluations in Chronic Alcoholics and Heroin Abusers

Computerized transaxial tomographic (CTT) scans and the Halstead-Reitan Neuropsychological Battery were administered to 42 paid male volunteers (15 chronic alcoholics, 15 heroin abusers, and 12 matched control subjects). CTT scans revealed that only 1 of the chronic alcoholics had a ventricle/brain (V/B) index larger than normal. One unexpected finding was that the heroin abusers had significantly smaller sulci and V/B indices. Neuropsychological assessments of the alcoholics and heroin abusers revealed functional impairment in a majority of cases; the alcoholics were twice as likely as opiate abusers to show impairment.

The effect of marijuana on carbohydrate metabolism.

The authors observed the effect of marijuana on carbohydrate metabolism in fed and fasting states in chronic marijuana users. They found no hypoglycemia in 7 patients who were given marijuana after fasting for 24-72 hours. They also found no significant difference in carbohydrate tolerance and no hypoglycemia during an oral glucose tolerance test in 10 patients who smoked placebo or marijuana on alternate days. They conclude that marijuana has no effect on carbohydrate metabolism in the fed or the fasted state in well-nourished chronic marijuana users.

Exclusion of linkage between alcoholism and the MNS blood group region on chromosome 4q in multiplex families.

Polymorphic DNA markers on the long arm of chromosome 4 were used to examine linkage to alcoholism in 20 multiplex pedigrees. Fifteen loci were determined for 124 individuals. Lod scores were calculated assuming both dominant and recessive disease modes of inheritance, utilizing incidence data by age and gender that allow for correction for variable age of onset and frequency of the disorder by gender. Under the assumption that alcoholism is homogeneous in this set of pedigrees, and that a recessive mode with age and gender correction is the most appropriate, the total lod scores for all families combined were uniformly lower than -2.0. This suggests an absence of linkage between the putative alcoholism susceptibility gene and markers in the region of the MNS blood group (4q28-31), a region for which we had previously found suggestive evidence of linkage to alcoholism. The 100 cM span of chromosome 4 studied includes the class I alcohol dehydrogenase (ADH) loci. Using the recessive mode, no evidence for linkage to alcoholism was found for the markers tested, which spanned almost the entire long arm of chromosome 4. Under the dominant mode, no evidence for linkage could be found for several of the markers.

Association and linkage studies of the TAQI A1 allele at the dopamine D2 receptor gene in samples of female and male alcoholics.

To address the controversy surrounding DRD2 and alcoholism, we performed linkage and association studies utilizing alcoholic men from high-density families largely uncontaminated by other psychopathology and female alcoholics for whom secondary drug dependence (averaging 10 years later onset) was a prominent feature. The males and females were combined for a total of 52 alcoholics, and compared to 30 controls screened for the absence of alcoholism and other psychopathology, revealing a significant association between the frequency of the TaqI A1 allele and alcoholism. However, linkage and family-based association studies conducted on 20 families of male alcoholics found no evidence for association or linkage between Taq A and alcoholism. The results of our population-based association study, placed in the context of the literature, suggest that minimizing psychopathology in control groups is probably a more important explanation for divergent results than either sampling error or population stratification. When combined with the complete lack of within-family evidence, we concluded that the association, while not appearing to be artifactual, is not specific to the alcoholism phenotype, per se.

Segregation analysis of alcoholism in high density families: a replication.

We have previously reported segregation analysis of alcoholism in 35 multigenerational families, each ascertained through a pair of male alcoholics by using the mixed model implemented by POINTER. This analysis suggested that liability to alcoholism was, in part, controlled by a major effect with or without additional multifactorial effects. The hypothesis that the major effect was explained by a single genetic locus with strictly mendelian transmission was rejected. The purpose of the present analysis was to use the regressive model implemented by the REGD program from the Statistical Analysis for Genetic Epidemiology computer package (S.A.G.E.) to confirm by replication that a major effect was present in these 35 families. Evidence for the major effect found in Pointer was replicated in the present analysis by using S.A.G.E. Also, we found strong evidence for parental effects that were independent of the major locus transmission from ancestral relatives to children. Mendelian transmission of this major effect was rejected when models incorporated parental effects. When the major effect was calculated adjusting for parental phenotypes, the relative risk of affection for children was about twice as high with affected parents vs. unaffected parents.

Personality traits and dopamine receptors (D2 and D4): linkage studies in families of alcoholics.

Activation of the mesolimbic dopamine pathway appears to promote drug- and alcohol-seeking behavior in laboratory animals. Results for association and linkage analysis between various alcohol dependence phenotypes and the dopamine receptors have been quite mixed. Similarly, both positive and negative results have been presented concerning dopamine receptor genes and temperament. Cloninger has postulated that the novelty seeking factor from the Tridimensional Personality Questionnaire (TPQ) may be related to the dopamine neurotransmitter system. As novelty seeking is a trait of some importance for substance-dependent individuals, our goal was to test this relationship within a sample of families of alcoholics. No evidence favoring linkage between D2, D4, or DAT1 was found for TPQ novelty seeking. However, the harm-avoidance trait from the TPQ showed evidence for linkage to both the D4 and one of the D2 loci (TaqI A). The Multidimensional Personality Questionnaire (MPQ) was used to provide converging evidence for these results. The TPQ harm-avoidance scale loads heavily on introversion (worry, pessimism, shyness), characteristics that may be especially salient in alcoholic families. Thus, planned comparisons were made between selected MPQ traits measuring the affective dimension (negative affectivity, stress reaction, alienation, and well-being). We find evidence favoring linkage between the D2 and D4 receptor loci and these MPQ traits, with stronger evidence being seen for the D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:634-641, 1999.

Linkage studies of D2 and D4 receptor genes and alcoholism.

The purpose of the present study was to evaluate two polymorphisms near the D2 receptor gene (TaqI A RFLP and C microsatellite) and a VNTR for D4. A nonparametric linkage (NPL) technique, SIBPAL, was used to test for the presence or absence of linkage in 54 multiplex alcoholic families. These families had been ascertained through two alcoholic proband siblings in order to increase the density of alcoholic cases within these pedigrees. Phenotypic definitions of alcoholism were manipulated in an effort to determine the impact of severity (signs of physical dependence, early age of onset, presence of antisocial personality disorder) on the likelihood of finding positive evidence for linkage. A regression analysis that simultaneously evaluated the allele sharing identical by descent for Feighner criteria alcoholism in affected, unaffected, and discordant sib pairs (SIBPAL) for two D2 polymorphisms and the D4 polymorphism gave no evidence for linkage. Phenotypes associated with greater alcoholism severity (presence of physical dependence symptoms, earlier onset, or comorbid antisocial personality disorder) revealed some evidence for linkage. The presence of one or more physical dependence symptoms in combination with Feighner criteria alcoholism provided some evidence favoring linkage (TaqI A and D4). Alcoholics with an earlier onset of alcoholism showed some evidence for linkage especially when the presence of physical dependence was required (e. g., morning drinking, wanted to stop drinking but could not, binges or benders, and evidence of withdrawal symptoms). Finally, alcoholics with antisocial personality disorder differed significantly in their allele sharing from nonalcoholics for both D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:676-685, 1999.

A comparison of two benzodiazepine hypnotics administered with alcohol.

Two benzodiazepine hypnotics were administered alone or in combination with alcohol to normal male volunteers. In the doses given, alcohol potentiated the effects of the benzodiazepines on some but not all performance measures.

Acquired preference for morphine but no d-amphetamine as a result of saccharine adulteration.

Consumption of morphine sulfate and d-amphetamine was studied in two groups of rats. In a choice situation, preference for both drugs remained low after 46 days of drinking. In two additional groups morphine and d-amphetamine solutions were prepared with 1% saccharine. Morphine drinking was significantly increased by saccharine adulteration, whereas drinking of amphetamine solutions decreased. Addition of saccharine to morphine solutions increased drinking in more than a simple additive way. Saccharine facilitates the acquisition of drug-directed behavior. The slope of the acquisition trials for the morphine-saccharine group was significantly different from horizontal (O-slope) and significantly different from the slope found for the morphine without saccharine group.

Effects of L-tryptophan and ethanol on sleep parameters in the rat.

Sleep parameters were monitored following (1) a single 2 g/kg oral dose of ethanol, (2) an oral dose of L-tryptophan (600 mg/kg), and (3) administration of both drugs simultaneously. Ethanol reduced REM and increased slow wave significantly. The effects of L-tryptophan were apparent only in the case of one parameter, REM latency. Administration of both drugs resulted in a significantly shorter REM latency than that observed for ethanol alone. Results are discussed in terms of possible changes in the biosynthesis of 5-HT.