Alcoholism is a complex disease determined by both genetic and environmental components that exerts a devastating economic and social impact worldwide. The complexity of this disease makes the elucidation of candidate genes for the susceptibility to alcoholism difficult in human populations, however, mouse model systems replicate many aspects of the disease and represent an excellent system for the investigation of the genetic contributions to alcoholism. One component of alcoholism that can be investigated in mouse models is the predisposition to high alcohol consumption. Selectively bred and inbred mice differ markedly in the level of voluntary alcohol intake using a two-bottle choice paradigm. The phenotype of voluntary alcohol consumption in mice is a complex trait and a genetic comparison between mouse models with similar levels of alcohol intake should identify genes that contribute to the predisposition for alcohol consumption. Three different studies were completed at the University of Texas and candidate genes involved in the predisposition to high alcohol consumption in mice were identified through the use of brain transcriptome analysis. In the first study, 3,800 transcripts were identified that were divergent between 3 selected lines and 6 isogenic strains of mice known to differ in voluntary alcohol consumption. This list was filtered to reveal candidate genes associated with alcohol preference on mouse chromosome 9: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, Zfp291. In the second study, analysis of voluntary alcohol intake and brain gene expression between two closely related inbred mouse substrains separated for nearly fifty years revealed divergent alcohol consumption as well as genetic variation between the substrains. Finally, the third study revealed dominant and overdominant patterns of expression in an F1 hybrid that voluntarily consumed more alcohol than either inbred parental strain. The microarray datasets analyzed here represent an important first step in the elucidation of the genetic determinants of high alcohol consumption in mice and will be influential in the discovery of genes that play a role in vulnerability to alcoholism in humans.

Indiana University-Purdue University Indianapolis (IUPUI) / Genetic vulnerability to alcoholism is theorized to be caused by multiple interacting genetic loci, each with a small to modest effect combining under certain environmental influences to contribute to vulnerability to ethanol dependence. Animal models such as selectively bred rodent lines can be used to address this hypothesis of genetic vulnerability. High-drinking lines are implicitly assumed by many to be evidence of high ethanol reinforcement without consideration for variables such as differential pre- and post ingestive effects, low response to alcohol or novelty-seeking. Therefore, it is an open question as to whether animal studies support the idea that genetic differences in free-choice drinking are correlated with genetic differences in other assessments of ethanol-reinforced behavior, including those utilizing operant and classical conditioning. Thus, the present study utilizes selectively bred High- and Low- Alcohol Preferring mice tested for operant intravenous alcohol administration to address the hypothesis that High Alcohol Preferring mice would show evidence of greater alcohol reinforcement than their selectively bred opposite, Low Alcohol Preferring mice. Evidence for greater reinforcement was supported by High Alcohol Preferring mice voluntarily pressing a lever to administer an intravenous dose of alcohol in a two lever choice paradigm, administering higher doses of intravenous alcohol, and tracking the location of the active alcohol lever during a lever reversal procedure in comparison to Low Alcohol Preferring mice. This study supports the High- and Low- Alcohol Preferring mice as a useful genetic model of alcohol-related vulnerability even when utilizing a route of administration that bypasses the digestive system.

The primary purpose of the present study was to investigate a specific area of cognitive functioning to determine if any differences exist between adult children of alcoholics and controls in the processing of emotionally laden word cues. Of secondary importance was the investigation of group differences in self-esteem, extroversion, neuroticism, and attentional control. A modified version of the Stroop Colour Naming Task was used to investigate selective processing of word cues in a sample of 37 adult children of alcoholics (ACOAs) and 37 adult children of non alcoholics (non ACOAs). All subjects were university students who volunteered for the study. The original form of this task required subjects to name the color of ink in which a word was printed while ignoring word content. Modified versions of this task substitute target words and control words for the words standardly used in order to investigate attentional bias for relevant word cues. As predicted, ACOAs were significantly slower than non ACOAs on this task. There was also a significant group x word type interaction. Compared to non ACOAs, ACOAs displayed a significant attentional bias in favor of alcohol and social threat words compared to neutral and positive words as evidenced by increased response times on the Stroop Task. There was also a significant main effect for word type with response time slowest for alcohol words and fastest for positive words. There were no significant group differences in self-esteem, extroversion, neuroticism, or attentional control. The results were discussed in terms of a generalized attentional deficit for the overall slower response time exhibited by the ACOA group. The more specialized Stroop effect of attentional bias for alcohol and social threat words was discussed in terms of the development of danger schemata based on previous life experiences perceived to be threatening. / Graduation date: 1992

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The dopamine transporter, the principle binding site for such drugs of abuse as cocaine and amphetamines, has a critical role in limiting dopamine availability. Several lines of evidence, including variation of DAT density in human alcoholics and in vervet monkeys with a preference for alcohol, have implicated this locus as a candidate gene, which might increase vulnerability to alcoholism. The objective of this study was to identify polymorphisms in the regulatory region of the dopamine transporter and determine whether there was an association between any of the alleles and alcoholism. Five polymorphisms were identified: three in humans and two in vervet monkey subjects. Mutation analysis of this locus may be a critical step in identifying alleles which increase susceptibility to alcohol abuse in humans and vervet monkeys.

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The primary focus of the present thesis is the exploration of factors that influence the dopamine (DA) neuron by examining the expression of the dopamine transporter (DAT), a marker of the DA neuron. The secondary focus of this thesis is on the serotonin neuron and in particular the serotonin transporter (SERT), a marker of the serotonin neuron. To this end three distinct and separate models have been employed. The goals of this thesis were: (1) to test the hypothesis that monoamine oxidase inhibition during development alters serotonergic innervation in the cortex and raphe, while not affecting relative DA innervation of nigrostriatal pathway, (2) to test the hypothesis that elevated brain levels of hypoxanthine (Hx) deleteriously affect the DA neuron, and (3) to test the hypothesis that densities of DAT and SERT in brainstem cell body regions distinguish alcohol-preferring vervet monkeys with different behavioral patterns of ethanol consumption. / Alterations in the activity of monoamine oxidase (MAO), a degradative enzyme that plays an important role in regulating levels of monoamine transmitters, may have a profound effect on brain development. The present study investigates relative DA and serotonin innervation of cortical and subcortical areas, measured by DAT and SERT densities, following MAO inhibition (A or B or A+B) in mice throughout gestation and early post-natal development. DAT binding was unaltered within the nigrostriatal pathway. The most significant finding reported here is that the combined MAO-A+B inhibition significantly reduced SERT binding by 25% in both the cortex and raphe nucleus. Lower levels of SERT binding were apparent during the early post-natal period (PND 14), a period during which pups were still exposed to MAO inhibitors in the dam's milk, but also persisted into later life (PND's 35 and 90) after inhibitors were no longer being administered. Persistent effects were restricted to cortex and raphe, suggesting a relative vulnerability of these regions to alterations in monoamine transmitter levels during development. / The second study presents data demonstrating that Hx delivered intracerebroventricularly significantly reduces the number of tyrosine hydroxylase immunoreactive cells (TH-ir) in the substantia nigra by 22% and 30%, at 7 and 21 days, respectively. After 3 days of Hx administration, striatal DA and serotonin were elevated over control levels by 22% and 25%, respectively, but returned to control levels by 7 days. The serotonin metabolite 5-HIAA was elevated after 3 days of Hx, but levels of DA metabolites were not different from control. Locomotion, a behavior thought to be related to DA transmission, was elevated following Hx treatment, as were presynaptic markers of the DA system such as DAT and TH protein levels. The persistent reduction in TH positive cell numbers suggests that Hx damages or kills DA neurons. The increase in intracellular DA at early time points suggests that Hx might interfere with DA release, possibly by temporarily inactivating DA neurons. These findings are consistent with the hypothesis that Hx, a purine significantly elevated in blood and CSF of Lesch-Nyhan patients, maybe involved in DA dysfunction. / Studies on alcohol abuse have focused on the mesolimbic DA pathway and the serotonergic influence within this pathway. Here we report that abstinent binge-drinking monkeys have significant reductions of SERT binding, and to a lesser extent, DAT binding in the midbrain region, while abstinent heavy-drinking subjects have elevated levels of DAT binding, as compared to controls. Both mesolimbic and nigrostriatal pathways are affected. CSF levels of both HVA and 5-HIAA substantiate the neuroanatomical differences between binge- and heavy-drinking vervets. Taken together, these findings provide a neurochemical profile with which to further distinguish subtypes of alcohol-preferring vervet monkeys.

Rationale. Definition of complex behavioral disorders is generally phenomenological in nature and guided by pragmatic, rather than genetic, concerns. Consequently, important aspect of genetic analysis is the search for novel phenotypic definitions from the familial/genetic perspective. SLI study 1. SLI denotes an inability to acquire normal language in the absence of peripheral hearing impairment, neurological disorder, and mental retardation. Sibling resemblance for several theoretically derived specific components of the SLI phenotype was examined in families of SLI children. In 38 sib-pairs from 10 French-speaking pedigrees, Verb Tense Morphology sub-tests (Real and Non-real Words) showed nonparametric correlations of 0.39 and 0.35, respectively (p < 0.05, 2-tailed). In a densely affected Anglophone pedigree, 41 sib-pair showed familial resemblance with respect to Derivational Morphology (r = 0.52, p < 0.01). SLI study 2. Family history study in 27 families examined the relationship between attention deficit/hyperactivity in SLI children and familial risk of speech/language disorders. Higher odds of speech/language disorders were observed in first-degree relatives of 13 SLI children who also had a medical record of attention deficit/hyperactivity (15/27 vs. 4/46, p = 0.001). Alcoholism study 1. Latent class analysis (LCA) including gender and 15 antisocial behaviors (>15yr) was performed in 236 broadly ascertained alcohol-dependent subjects (121 males, 115 females). Evidence for 3 qualitative behavioral classes was obtained: Socially Adjusted Adults, SAA; Antisocial Non-Aggressive Adults, ANAA; and Antisocial Aggressive Adults, AAA. In both, genders, the AAA class had the earliest age of onset for alcohol dependence (p = 0.001), more alcoholic first-degree relatives and more of other psychopathology. In females, the ANAA class was intermediate. In the ANAA males, socially adjusted childhood behavior differentiated the late onset from the intermediate ons