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

Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202-4887, United States.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 07/2008; 89(4):481-98. DOI: 10.1016/j.pbb.2008.01.023
Source: PubMed


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. Animals were killed 24 h after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p<0.01 level in named genes: 55 between SAC and water; 215 between EtOH and water, and 243 between EtOH and SAC. In the case of the AMYG (p<0.01), there were 48 between SAC and water, 23 between EtOH and water, and 63 between EtOH and SAC group. Gene Ontology (GO) analysis indicated that differences in the ACB between the EtOH and SAC groups could be grouped into 15 significant (p<0.05) categories, which included major categories such as synaptic transmission, cell and ion homeostasis, and neurogenesis, whereas differences between the EtOH and water groups had only 4 categories, which also included homeostasis and synaptic transmission. Several genes were in common between the EtOH and both the SAC and water groups in the synaptic transmission (e.g., Cav2, Nrxn3, Gabrb2, Gad1, Homer1) and homeostasis (S100b, Prkca, Ftl1) categories. Overall, the results suggest that changes in gene expression in the ACB of iP rats are associated with the reinforcing effects of EtOH.

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Available from: Richard L Bell, Sep 27, 2014
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    • "Bottles were also placed on empty cages to provide an index of spillage due to bottle handling, and this spillage was subtracted daily from the volume consumed by the rats. We first assayed for AAV effects upon the intake and preference for palatable non-alcoholic fluids by presenting rats with 0%, 0.00625%, and 0.0125% saccharin (w/v) (Rodd et al., 2008) for 5 days (Monday to Friday). The following week, rats were given access to 0% vs. 5% sucrose (e.g., Cozzoli et al., 2009) for 5 days. "
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    ABSTRACT: In murine models of alcoholism, the glutamate receptor scaffolding protein Homer2 bidirectionally regulates alcohol intake. Although chronic alcohol drinking increases Homer2 expression within the core subregion of the nucleus accumbens (NAc) of alcohol-preferring P rats, the relevance of this neuroadaptation for alcohol intake has yet to be determined in rats. Thus, the present study employed an adeno-associated viral vector (AAV) strategy to over-express and knock down the major rodent isoform Homer2b within the NAc of both P and outbred Wistar rats to examine for changes in alcohol preference and intake (0-30% v/v) under continuous-access procedures. The generalization of AAV effects to non-drug, palatable, sweet solutions was also determined in tests of sucrose (0-5% w/v) and saccharin (0-0.125% w/v) intake/preference. No net-flux in vivo microdialysis was conducted for glutamate in the NAc to relate Homer2-dependent changes in alcohol intake to extracellular levels of glutamate. Line differences were noted for sweet solution preference and intake, but these variables were not affected by intra-NAc AAV infusion in either line. In contrast, Homer2b over-expression elevated, while Homer2b knock-down reduced, alcohol intake in both lines, and this effect was greatest at the highest concentration. Strikingly, in P rats there was a direct association between changes in Homer2b expression and NAc extracellular glutamate levels, but this effect was not seen in Wistar rats. These data indicate that NAc Homer2b expression actively regulates alcohol consumption by rats, paralleling this previous observation in mice. Overall, these findings underscore the importance of mesocorticolimbic glutamate activity in alcohol abuse/dependence and suggest that Homer2b and/or its constituents may serve as molecular targets for the treatment of these disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Alcohol (Fayetteville, N.Y.) 07/2015; 49(6). DOI:10.1016/j.alcohol.2015.03.009 · 2.01 Impact Factor
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    • "Using a similar approach we compiled findings from several transcriptional profiling studies that have identified differentially expressed genes from alcohol-related studies on D. melanogaster (Morozova et al. 2006, 2007, 2009, 2011; Urizar et al. 2007; Awofala 2010; Kong et al. 2010); from alcohol-related expression studies done on mice (Xu et al. 2001; Daniels and Buck 2002; Tabakoff et al. 2003; Hitzemann et al. 2004; Saito et al. 2004; Treadwell and Singh 2004; Kerns et al. 2005; MacLaren et al. 2006; Mulligan et al. 2006, 2011; Saba et al. 2006; wang et al. 2007; Denmark and Buck 2008; wolstenholme et al. 2011), and transcriptional profiling data on rats (Rimondini et al. 2002; edenberg et al. 2005; worst et al. 2005; Carr et al. 2007; Kimpel et al. 2007; Rodd et al. 2008), and identified human orthologs. In addition, we analyzed six published transcriptional profiling data sets performed on different areas of postmortem human brains and also included candidate genes for alcohol-related phenotypes from the HuGe Navigator database (Lewohl et al. 2000; Mayfield et al. 2002; Sokolov et al. 2003; Iwamoto et al. 2004; Flatscher-Bader et al. 2005; Liu et al. 2006a; Guo et al. 2009). "
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    ABSTRACT: Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00438-013-0808-y) contains supplementary material, which is available to authorized users.
    MGG Molecular & General Genetics 01/2014; 289(3). DOI:10.1007/s00438-013-0808-y · 2.73 Impact Factor
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    • " was at least 1 . 4 ( Tables 7 and 8 ) . There was excellent agreement between the microarray and qRT - PCR results . In addition , previous studies from our laboratory reported good agreement , in 30 of 32 genes tested , between the data obtained with microarrays and the results found with qRT - PCR ( Bell et al . , 2009 ; Kimpel et al . , 2007 ; Rodd et al . , 2008 ) . For example , Gsta4 ( Table 7 ) has been previously validated with qRT - PCR in 3 different brain regions of inbred P vs . inbred NP rats ( Kimpel et al . , 2007 ) ."
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    ABSTRACT: The objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line-pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol-preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line-pairs. Microarray analysis revealed up to 1772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line-pairs, but not for all 5 line-pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line-pairs indicated 1014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4-6 individual named genes that significantly differed across up to 3 line-pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line-pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line-pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line-pairs.
    Alcohol (Fayetteville, N.Y.) 10/2013; 47(7). DOI:10.1016/j.alcohol.2013.08.004 · 2.01 Impact Factor
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