Quantitative Trait Loci Mapping for Ethanol Sensitivity and Neurotensin Receptor Density in an F₂ Intercross Derived From Inbred High and Low Alcohol Sensitivity Selectively Bred Rat Lines

Abstract

The results indicate that segregating populations derived from the IHAS and ILAS strains can be used for mapping ethanol sensitivity QTL. The chromosome 2 LORR QTL may confer variation in ethanol metabolism, whereas the chromosome 5 LORR/BECrrr QTL likely mediates central nervous system ethanol sensitivity. The small number or absence of QTL for BEC1, AFT, and NTR1 receptor density suggests that genetic variation for these traits is minimal in the IHAS/ILAS strains and/or the effect size of QTL for these traits is too small to be mapped efficiently in this sample of F(2) rats. The ultimate identification of genes underlying these alcohol sensitivity QTL will contribute to our understanding of the actions of alcohol in the central nervous system if not to a deeper understanding of the genetic risk factors for alcoholism.

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

“…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.…”

“…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).…”

“…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).…”

“…Slit homolog 1 (Drosophila), higher in the iP line, has been implicated in processes related to neuroplasticity (Table 9), specifically in axon guidance (Chang et al, 2006;Long et al, 2004;Thompson et al, 2006). One of the 21 differentially expressed genes in the HIPP, ribosomal protein S2, was 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). Some of these differences in the HIPP between iP and iNP rats may be associated with the differences in the development and/or persistence of tolerance to the motor impairing effects of alcohol observed for the parent lines (Bell et al, 2001;Gatto et al, 1987aGatto et al, ,1987bWaller et al, 1983).…”

“…Gill et al (1996) have also reported higher catalase activity in the CNS of P rats compared to NP rats. Two of the 15 differentially expressed genes in the ACB 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), that is, ribosomal protein S2 and proteasome (prosome, macropain) subunit, alpha type 5 (Table 5). Some of the differences in the ACB could be related to the disparate alcohol drinking characteristics of the iP and iNP strains.…”