Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats.

Background: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats.

Methods: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats.

Quantitative trait locus for body weight identified on rat chromosome 4 in inbred alcohol-preferring and -nonpreferring rats: potential implications for neuropeptide Y and corticotrophin releasing hormone 2.

The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed using bidirectional selective breeding for alcohol consumption (g/kg/day) and alcohol preference (water:ethanol ratio). During a preliminary study, we detected a difference in body weight between inbred P (iP) and inbred NP (iNP) rats that appeared to be associated with the transfer of the Chromosome 4 quantitative trait locus (QTL) seen in the P.NP and NP.

Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats.

The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake. The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains. The HAD×LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses.

Identification of genes influencing skeletal phenotypes in congenic P/NP rats.

We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference.

Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats.

Background: Selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ greatly in alcohol preference, in part due to a highly significant quantitative trait locus (QTL) on chromosome 4. Alcohol consumption scores of reciprocal chromosome 4 congenic strains NP.P and P.

Identification of a novel cytosolic aldehyde dehydrogenase allele, ALDH1A1*4.

This paper reports the identification of a novel cytosolic aldehyde dehydrogenase 1 ( ALDH1A1 ) allele. One hundred and sixty-two Indo-Trinidadian and 85 Afro-Trinidadian individuals were genotyped. A novel ALDH1A1 allele, ALDH1A1*4 , was identified in an Indo-Trinidadian alcoholic with an A inserted at position -554 relative to the translational start site, +1.

Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day).

From QTL to candidate gene: a genetic approach to alcoholism research.

A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively.

Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats.

The current study examined the effects of operant ethanol (EtOH) self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water-water, EtOH (15% v/v)-water, or saccharin (SAC; 0.0125% g/v)-water.

Ethnic differences in level of response to alcohol between Chinese Americans and Korean Americans.

Objective: Koreans have higher rates of alcohol-use disorders and family history of alcoholism, compared with Chinese. These differences likely reflect both environmental and genetic influences. One genetically influenced characteristic that may contribute to these ethnic differences is level of response to alcohol.

Sex-specific genetic loci for femoral neck bone mass and strength identified in inbred COP and DA rats.

Introduction: Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans identified chromosomal regions linked to hip size and bone mass. Animal models, particularly the inbred rat, serve as complementary approaches for studying the genetic influence on hip fragility.

Drd2 expression in the high alcohol-preferring and low alcohol-preferring mice.

The high alcohol-preferring (HAP) and low alcohol-preferring (LAP) mice were selectively bred for differences in alcohol preference and consumption. Recently, a large-effect QTL was identified on chromosome 9. The peak for this QTL is near the Drd2 (dopamine receptor 2) locus.

Genetic loci affecting bone structure and strength in inbred COP and DA rats.

Previous studies have shown that the Copenhagen 2331 (COP) and Dark Agouti (DA) rats have significant differences in bone structure and strength despite their similar body mass. Thus, these inbred rat strains may provide a unique resource to identify the genetics underlying the phenotypic variation in bone fragility. A sample of 828 (405 males and 423 females) COPxDA F2 progeny had extensive phenotyping for bone structure measures including cortical bone area and polar moment of inertia at the femur midshaft and total, cortical and trabecular bone areas, for the lumbar vertebra 5 (L5).

Stability of heavy episodic drinking in Chinese- and Korean-American college students: effects of ALDH2 gene status and behavioral undercontrol.

Objective: A previous cross-sectional study showed that, among individuals of Chinese and Korean descent, possession of ALDH2*2 alleles was associated with protection against alcohol dependence, whereas conduct disorder was associated with increased vulnerability to dependence. The purpose of this longitudinal study was to examine the roles of ALDH2 and behavioral undercontrol (a temperamental trait that is associated with conduct disorder) in stability of heavy episodic drinking.

Method: Chinese- and Korean-American college students (N = 336; 51% female), who had initiated alcohol use before study enrollment, provided information on drinking habits during their freshman and sophomore years.

Association of the aldehyde dehydrogenase 2 promoter polymorphism with alcohol consumption and reactions in an American Jewish population.

Background: Reduction in activity of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme due to genetic deficiency causes reactions related to alcohol consumption and lowers the risk of alcoholism. ALDH2*2 is the only functionally significant polymorphism of the ALDH2 gene. An additional polymorphic locus in the promoter (G to A substitution approximately 360 bp from the translation start site) may influence ALDH2 activity through effects on transcriptional activity.

Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago.

The population of Trinidad and Tobago is composed mainly of people of East Indian (Indo-Trinidadians) and African (Afro-Trinidadians) ancestry. Differences in alcoholism rates exist between these two ethnic groups, and researchers have investigated whether these differences can be explained in part by variations in the genes encoding the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) 1B and 1C, and aldehyde dehydrogenase (ALDH) 1 and 2. Studies have demonstrated that a certain variant of the gene encoding ADH1B (ADH1B*3) is associated with a reduced risk of alcoholism in Afro-Trinidadians, as is a variant of the gene encoding ADH1C (i.

Effect of ADH1B genotype on alcohol consumption in young Israeli Jews.

Background: The alcohol dehydrogenase 1B (ADH1B) genotype affects the risk for alcoholism, with elevated prevalence of a protective allele in Jews. Alcohol consumption is increasing among younger Israeli Jews, reflecting environmental influences. We investigated whether the relationship of ADH1B genotype with alcohol consumption differed between younger and older adult Israelis.

Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions.

The objective of this study was to determine if there are innate differences in gene expression in selected CNS regions between inbred alcohol-preferring (iP) and -non-preferring (iNP) rats. Gene expression was determined in the nucleus accumbens (ACB), amygdala (AMYG), frontal cortex (FC), caudate-putamen (CPU), and hippocampus (HIPP) of alcohol-naïve adult male iP and iNP rats, using Affymetrix Rat Genome U34A microarrays (n = 6/strain). Using Linear Modeling for Microarray Analysis with a false discovery rate threshold of 0.

Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains.

Background: A highly significant quantitative trait locus (QTL) on chromosome 4 that influenced alcohol preference was identified by analyzing crosses between the iP and iNP rats. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) exhibited the expected increase in alcohol consumption compared with the iNP background strain.

Association of ALDH1 promoter polymorphisms with alcohol-related phenotypes in Trinidad and Tobago.

Objective: Two polymorphisms in the promoter region of the gene encoding cytosolic aldehyde dehydrogenase (ALDH1A1), ALDH1A1*2 and ALDH1A1*3, have recently been identified. The present study sought to determine whether an association exists between ALDH1A1 genotypes, alcohol dependence, drinking history, and liver function tests in the two major ethnic groups of Trinidad and Tobago (TT).

Method: The participants in this study were 137 alcohol dependents of either East Indian ancestry (Indo-TT) or African ancestry (Afro-TT) and 108 controls matched by age, gender, and ethnicity.

Association of the ADHIB*3 allele with alcohol-related phenotypes in Trinidad.

Background: Two of the class I alcohol dehydrogenase (ADH) genes located on chromosome 4 (ADH1B and ADH1C) encode for multiple isozymes that differ in their kinetic properties. At the ADH1B locus, 3 polymorphisms are present (ADH1B(*)1, ADH1B(*)2, ADH1B(*)3). ADH1B(*)2 (found mostly in individuals of East Asian and Jewish descent) and ADH1B(*)3 (found mostly in individuals of African decent) alleles encode for a more active enzyme variants than ADH1B(*)1 and the presence of these alleles has been associated with protection from alcohol dependence.

Regulation of alpha-synuclein expression in alcohol-preferring and -non preferring rats.

The alpha-synuclein (Snca) gene is expressed at higher levels in alcohol-naïve, inbred alcohol-preferring (iP) rats than in alcohol-non preferring (iNP) rats. Snca modulates dopamine transmission and the dopamineregic system, which play a role in mediating the rewarding properties of alcohol consumption. Thus, understanding regulation of Snca gene expression could provide insight into the relationship of Snca and alcohol consumption.

Associations of variations in alcohol dehydrogenase genes with the level of response to alcohol in non-Asians.

Background: Risk and protective factors for alcohol use disorders (AUDs) are complex and reflect both environmental and genetic factors. Genetic components account for about 50% of the variation and influence several phenotypes, including the level of response (LR) to alcohol as well as alcohol-metabolizing enzyme polymorphisms. Variations in the ADH1B and ADH1C genes may influence the LR to alcohol by increasing levels of acetaldehyde during alcohol metabolism, although most data on this question come from Asian populations.

ALDH2*2 is associated with a decreased likelihood of alcohol-induced blackouts in Asian American college students.

Objective: A recent report found the heritability estimate for alcohol-induced blackouts was 53%. The present study was designed to determine whether possession of two specific genetic variations, an aldehyde dehydrogenase ALDH2*2 allele and an alcohol dehydrogenase ADHIB*2 allele, were associated with lower rates of lifetime blackouts.

Method: Asian American college students (N=403) of Chinese and Korean descent were genotyped at the ALDH2 and ADHIB loci and assessed for lifetime alcohol-induced blackouts and the maximum number of drinks ever consumed in a 24-hour period.

Identification of QTLs influencing alcohol preference in the High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) mouse lines.

The High- and Low-Alcohol Preferring (HAP1/LAP1 and HAP2/LAP2) mouse lines were developed by selective breeding for differences in alcohol preference. They represent the only extant selectively bred mouse lines developed for this alcohol phenotype. Therefore, they provide a unique resource for QTL detection and mapping.