INIA - RSA Abstracts 2004

RSA 2006 Abstracts

Indiana University , Indianapolis

Gene Clusters with Differential Expression Between Inbred Alcohol-preferring and Non-preferring Rats May Contain Genes That Mediate Alcohol Preference: M. W. Kimpel; L. Li; W. N. Strother; H. J. Edenberg; W. J. McBride. Depts Psych, Med, Biochem & Mol Biol, and Med & Mol Genetics, Ctr Med Genomics, and Inst Psych Res, Indiana Univ Sch Med, Indianapolis, IN 46202-4887.

The objective of this study was to apply statistical methodology to functional genomic data to identify small chromosomal intervals with overall genomic heterogeneity that may fall within QTL regions for alcohol preference. Alcohol naïve inbred P rats (iP, strain 5C, n=6) and NP rats (iNP, strain 1, n=6) were sacrificed and mRNAs from 5 CNS regions were analyzed using standard oligonucleotide microarray techniques. Linear modeling on unpermuted and permuted data was used to calculate the probability that the overall differential expression of each 9 gene interval could have occurred by chance. Genes in resultant significant intervals were compared to those within known rat QTLs and were analyzed for significance using Gene Ontology (GO) categories. After merging intervals that overlapped or were immediately adjacent to each other, 36 unique intervals, containing 427 named genes, were identified as having significantly different median expression (FDR<0.015). Seven of the intervals (19.4%) and 141 of the genes (33.0%) were located within at least one rat ethanol-related QTL. These regions of overlap occurred on chromosomes 2, 4, 6, and 12. Two nearly adjacent intervals on chromosome 4, covering the range of 126-162 MBP, were overlapped by 3 alcohol QTLs. This region contains genes coding for, among others, a metabotropic glutamate receptor, a glutamate receptor binding protein, 2 GABA transporters, and thyrotropin releasing hormone. Several GO categories were over-represented within the set of genes contained in significant intervals (p<0.005) and included: transmission of nerve impulse, second-messenger-mediated signaling, central nervous system development, and voltage-gated potassium channel activity. Overall, the results of this study suggest that the combination of QTL analysis and gene expression data could give critical information toward identifying genes contributing to the risk for high alcohol drinking behavior. (AA07611, AA07462, AA13521 [INIA Project], AA13522 [INIA Project], and INGEN®). Abstract category: first – 1g; second 1d

REPEATED SCHEDULED DRINKING-IN-THE-DARK (DID) ACCESS TO ETHANOL AND ITS EFFECTS ON GENE EXPRESSION IN ADULT INBRED P RATS: R. L. Bell; Z. A. Rodd; M. W. Kimpel; W. N. Strother; R. Jerome; J. N. McClintick; J. M. Murphy; L. Lumeng; H. Edenberg; W. J. McBride. Department of Psychiatry, Indiana University School of Medicine, IUPUI, Indianapolis, IN 46202.

We have used a DID protocol to serve as a drinking model of binge-like E exposure in rats. In the present study, we examined changes in gene expression within the amygdala (AMYG) and nucleus accumbens (ACB) of adult male inbred alcohol-preferring (P) rats after 7 weeks of DID access to multiple concentrations of E (15% & 30% and ad lib water), compared with rats that had 7 weeks of 24-hr continuous
(CONT) access to multiple concentrations of E, or water (W) controls (n=6/group). For the DID protocol, rats had four 1-hr access periods to E, starting 1-hr after dark onset and separated by 2-hrs, across the dark-cycle. Rats were euthanized 11-hr following the last E access period, the AMYG and ACB dissected, RNA extracted and purified for microarray analysis, with Affymetrix Rat Genome 230 2.0 Array GeneChips.
A Welch's corrected t-test (alpha = 0.05) was used to assess group differences in gene expression between each E group and the W group. Within the AMYG, there were 1209 differences between the DID and W groups (e.g., increases in 5-HT1A and 5-HT2C receptor-, as well as GABA and glycine transporter, with decreases in GABA-A (delta) and purinergic PX2 receptor- as well as glutamate transporter-associated genes); and
1185 differences between the CONT and W groups (e.g., increases in ionotropic Glu alpha 1 and MACh3 receptor-, as well as choline and glutamate transporter-, with decreases in 5-HT2A and ionotropic Glu delta 2 receptor-associated genes). Within the ACB, there were 648 differences between the DID and W groups (e.g., increases in hypocretin 2, NACh(beta)2 and tachykinin NK1C7 receptor-, with decreases in A2 adenosine, MACh3 and tumor necrosis factor 1a receptor-, as well as GABA, glutamate and glycine transporter-associated genes); and 593 differences between the CONT and W groups (e.g., increases in histamine H3 and purinergic P2X4 receptor- with decreases in growth hormone, MACh5, NACh(beta)2, NPY Y-5 and retinoid X receptor-associated genes). Overall, these findings indicate that chronic E drinking alters gene expression for a number of neurotransmitter/neuromodulator-associated proteins, and that DID and CONT access conditions influence some of these alterations differentially. [AA07611, (AA13496, AA13521, AA13522 INIA Projects), INGEN(r)]

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