Confirmation of alcohol preference quantitative trait loci in the replicate high alcohol drinking and low alcohol drinking rat lines

Foroud, Tatiana; Ritchotte, Aimee; Spence, John P.; Liu, Lixiang; Lumeng, Lawrence; Li, Ting Kai; Carr, Lucinda G.

doi:10.1097/00041444-200309000-00004

Cited by 30 publications

(38 citation statements)

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“…Contrary to this hypothesis, the affected genes appear to be scattered across the genome, and, with the exception of NPY, none of these genes is located near known quantitative trait loci (QTL) for alcohol preference or consumption in rats. 33,34 Although, due to the relatively limited number of genes analysed, this conclusion must be regarded as preliminary. A true pathway or cluster assessment would require screens of at least ten times the present size, which is becoming feasible with the arrival of new generations of arrays for the rat genome.…”

Section: Discussionmentioning

confidence: 95%

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

et al. 2004

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Analyzing gene expression patterns in genetic models of alcoholism may uncover previously unknown susceptibility genes, and point to novel targets for drug development. Here, we compared expression profiles in alcoholpreferring AA rats with the alcohol-avoiding counterpart ANA line, and unselected Wistar rats. Cingulate cortex, Nc. accumbens, amygdala and hippocampus of each line were analyzed using the Afymetrix RN U34 arrays and dChip 1.1 software. Analysis of line-specific expression revealed 48 differentially expressed genes between AA and ANA rats. Elevated hippocampal neuropeptide Y (NPY) was found in ANA rats in agreement with previous studies. A cluster of MAP-kinases indicating altered signal transduction was upregulated within the Nc. Accumbens of the AA line, and is of particular functional interest. Within the amygdala, a more loosely inter-related cluster of cytoskeleton-associated genes may point to structural abnormalities. The observed dysregulations may contribute to the alcohol-preferring phenotype.

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Section: Discussionmentioning

confidence: 95%

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

et al. 2004

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“…The number of differences between the two inbred lines in each of the five individual regions ranged from 8 to 63, with the order of number of differences being AMYG > CPU > HIPP > ACB > FC (Table 1). Across regions, the total number of genes that demonstrated differential expression ranged from 8 to 54; the number of genes that were located within established alcohol QTLs Foroud et al, 2002Foroud et al, ,2003Radcliffe et al, 2004;Terenina-Rigaldie et al, 2003) ranged from 1 to 16. Table 2 lists the significant genes that were different within each region along with individual fold changes and gene symbols.…”

Section: Resultsmentioning

confidence: 99%

“…Thirteen of the 54 differentially expressed genes in the AMYG were located within established alcohol QTLs Carr et al, 1998Carr et al, ,2003Foroud et al, 2002Foroud et al, ,2003Radcliffe et al, 2004;Terenina-Rigaldie et al, 2003) (Table 5). The pathway involving caspase 3 (lower expression in iP rats) and interleukin-1 receptor-associated kinase 2 (higher expression in iP rats) is involved in the age-related decline in function of hippocampal cells (Lynch & Lynch, 2002).…”

Section: Within-region Analysismentioning

confidence: 99%

“…Although classified by GO as having a function in neurotransmission (Table 6), Shc3 is perhaps more appropriately thought of as playing a role in the regulation of neuronal development and synaptic function (Liu & Meakin, 2002). In the CPU, 8 of the 24 differentially expressed genes were located within established alcohol QTLs Carr et al, 1998Carr et al, ,2003Foroud et al, 2002Foroud et al, ,2003Radcliffe et al, 2004;Terenina-Rigaldie et al, 2003) (Table 5). Among these 8 genes, several are involved in protein formation, that is, ribosomal protein S2 heat shock protein 2, and zinc finger protein 386 (Kruppel-like).…”

Section: Within-region Analysismentioning

confidence: 99%

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

Kimpel

Strother

McClintick

et al. 2007

Alcohol

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107

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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 0.1, there were 16 genes with differential expression in the ACB, 54 in the AMYG, 8 in the FC, 24 in the CPU, and 21 in the HIPP. When examining the main effect of strain across regions, 296 genes were differentially expressed. Although the relatively small number of genes found significant within individual regions precluded a powerful analysis for over-represented Gene Ontology categories, the much larger list resulting from the main effect of strain analysis produced 17 over-represented categories (P <.05), including axon guidance, gliogenesis, negative regulation of programmed cell death, regulation of programmed cell death, regulation of synapse structure function, and transmission of nerve impulse. Co-citation analysis and graphing of significant genes revealed a network involved in the neuropeptide Y (NPY) transmitter system. Correlation of all significant genes with those located within previously established rat alcohol QTLs revealed that of the total of 313 significant genes, 71 are located within such QTLs. The many regional and overall gene expression differences between the iP and iNP rat lines may contribute to the divergent alcohol drinking phenotypes of these rats.

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“…Animal models of alcohol preference have been used to identify both chromosomal loci and candidate genes that may influence alcohol-drinking behavior Foroud et al, 2000;Grisel et al, 2002;Liang et al, 2003). The alcohol-preferring (P) andnonpreferring (NP) rat lines were developed through bidirectional selective breeding from a randomly bred closed colony of Wistar rats [Wrm: WRC(WI)BR] on the basis of alcohol consumption and preference (Li et al, 1991).…”

Section: Hhs Public Accessmentioning

confidence: 99%

Glutathione S‐Transferase 8‐8 Expression Is Lower in Alcohol‐Preferring Than in Alcohol‐Nonpreferring Rats

Liang

Habegger

Spence

et al. 2004

Alcoholism Clin & Exp Res

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Objective-A primary focus of alcohol research is to provide novel targets for alcohol treatment by identifying genes that predispose individuals to drink alcohol. Animal models of alcoholism developed by selective breeding are invaluable tools to elucidate both the genetic nature and the underlying biological mechanisms that contribute to alcohol dependence. These selected lines (high alcohol preferring and low alcohol preferring) display phenotypic and genetic differences that can be studied to further our understanding of alcohol preference and related genetic traits. By combining molecular techniques, genetic and physiological factors that underlie the cause of alcoholism can be identified.Methods-Total gene expression analysis was used to identify genes that are differentially expressed in specific brain regions between alcohol-naïve, inbred alcohol-preferring (iP) andnonpreferring (iNP) rats. Quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot, and sequence analysis were used to further characterize rat glutathione S-transferase .Results-Lower expression of rGST 8-8 mRNA was observed in discrete brain regions of iP compared with iNP animals, and these expression differences were confirmed. To determine additional expression patterns of rGST 8-8, we used in situ hybridization. Rat GST 8-8 was highly expressed in hippocampus, the choroid plexus of the dorsal third ventricle and the lateral ventricle, and ependymal cells along the dorsal third ventricle and the third ventricle. Western blot analysis showed that rGST 8-8 protein levels were lower in the hippocampus and the amygdala of iP compared with iNP. A silent single-nucleotide polymorphism in the coding region and three single-nucleotide polymorphisms in the 3′-UTR were identified in the rGST 8-8 cDNA.Conclusion-There is regional variation of rGST 8-8 expression in the brain, at both the mRNA and protein level, and the iP strain has lower innate rGST 8-8 levels than the iNP strain in discrete brain regions. Alcoholism is a complex disorder influenced by both environmental and genetic factors. The genetic contribution to alcoholism likely results from the action of multiple, possibly interacting genes. Identification of the genes that influence alcohol drinking is an important area of research in the alcohol field and has involved several strategies, including the use of human studies and the development of genetic animal models of alcoholism. Sequencing of the rat genome has revealed that most human genes have counterparts in the rat (Rat Genome Sequencing Project Consortium, 2004). Thus, identification of interesting genes in a rat model can provide candidate genes for specific diseases that can be evaluated further in humans. HHS Public AccessAnimal models of alcohol preference have been used to identify both chromosomal loci and candidate genes that may influence alcohol-drinking behavior Foroud et al., 2000;Grisel et al., 2002;Liang et al., 2003). The alcohol-preferring (P) andnonpreferring (NP) ...

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Confirmation of alcohol preference quantitative trait loci in the replicate high alcohol drinking and low alcohol drinking rat lines

Abstract: Further evaluation of each of these QTL regions is ongoing in a sample of HAD2xLAD2 F2 progeny currently being generated that will be used to assess the evidence of linkage in each of these QTL regions.

Cited by 30 publications

References 20 publications

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

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

Glutathione S‐Transferase 8‐8 Expression Is Lower in Alcohol‐Preferring Than in Alcohol‐Nonpreferring Rats

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