Changes in gene expression within the ventral tegmental area following repeated excessive binge-like alcohol drinking by alcohol-preferring (P) rats.
- Authors
- McBride, William J; Kimpel, Mark W; McClintick, Jeanette N; Ding, Zheng-Ming; Hauser, Sheketha R; Edenberg, Howard J; Bell, Richard L; Rodd, Zachary A
- Year
- 2013
- Journal
- Alcohol (Fayetteville, N.Y.)
- PMID
- 23714385
- DOI
- 10.1016/j.alcohol.2013.04.002
- PMCID
- PMC3704142
The objective of this study was to detect changes in gene expression in the ventral tegmental area (VTA) following repeated excessive binge-like ('loss-of-control') alcohol drinking by alcohol-preferring (P) rats. Adult female P rats (n = 7) were given concurrent access to 10, 20, and 30% EtOH for 4 1-h sessions daily for 10 weeks followed by 2 cycles of 2 weeks of abstinence and 2 weeks of EtOH access. Rats were sacrificed by decapitation 3 h after the 4th daily EtOH-access session at the end of the second 2-week relapse period. A water-control group of female P rats (n = 8) was also sacrificed. RNA was prepared from micro-punch samples of the VTA from individual rats; analyses were conducted with Affymetrix Rat 230.2 GeneChips. Ethanol intakes were 1.2-1.7 g/kg per session, resulting in blood levels >200 mg% at the end of the 4th session. There were 211 unique named genes that significantly differed (FDR = 0.1) between the water and EtOH groups. Bioinformatics analyses indicated alterations in a) transcription factors that reduced excitation-coupled transcription and promoted excitotoxic neuronal damage involving clusters of genes associated with Nfkbia, Fos, and Srebf1, b) genes that reduced cholesterol and fatty acid synthesis, and increased protein degradation, and c) genes involved in cell-to-cell interactions and regulation of the actin cytoskeleton. Among the named genes, there were 62 genes that showed differences between alcohol-naïve P and non-preferring (NP) rats, with 43 of the genes changing toward NP-like expression levels following excessive binge-like drinking in the P rats. These genes are involved in a pro-inflammatory response, and enhanced response to glucocorticoids and steroid hormones. Overall, the results of this study indicate that the repeated excessive binge-like alcohol drinking can change the expression of genes that may alter neuronal function in several ways, some of which may be deleterious.
Estimated total ethanol intakes (g/kg/day; top panel) by P rats given concurrent access to 10, 20, and 30% ethanol (with water freely available) for 4 1-hour sessions each day during the dark cycle. Estimated intakes (g/kg) for each of the 4 1-hour access sessions during weeks 7–10 are given in the bottom panel. Ethanol was given 5 consecutive days each week (no ethanol on weekends) over the 10 weeks of access. *Indicates significantly (p < .001) higher ethanol intakes compared to sessions 3–5. BECs sampled across multiple sessions during weeks 8–10 indicated: 1) 124 ± 14 mg% following 1st session; 2) 177 ± 19 mg% following the 2nd session; 3) 128 ± 16 mg% immediately prior to the 3rd session; and 4) 237 ± 20 mg% following the 4th session. Data are the means ± SEM (n = 7).
LLM interpretation
This figure consists of a line graph (top) and a grouped bar chart (bottom) showing ethanol intake in P rats over 10 weeks. The line graph shows total average intake (g/kg/day) remaining stable from weeks 1–5 before significantly increasing from week 6 through 10 (*p < .001). The bar chart breaks down intake (g/kg) by session (1st–4th) for weeks 7–10, showing varying consumption levels across the four daily sessions.
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