Changes in gene expression within the ventral tegmental area following repeated excessive binge-like alcohol drinking by alcohol-preferring (P) rats

Abstract

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-hour 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 hours 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.

Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking

“…These previous studies predominantly used the hippocampus, ventral tegmental area, accumbens, amygdala or sub-regions of these areas. (Bell et al, 2009; Kimpel et al, 2007; McBride et al, 2013a; McBride et al, 2012; McBride et al, 2013b; McBride et al, 2010; Rodd et al, 2008). None examined the DRN.…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…P rats readily attain pharmacologically relevant blood alcohol concentrations (BACs, 80 to 250 mg%: this would approximate 0.08 to 0.25 in forensic terms, the latter under operant binge-like conditions) (Bell et al, 2013, 2014, 2011; Bell, Rodd, Lumeng, Murphy, & McBride, 2006; Bell, Rodd, Sable, et al, 2006; Bell, Rodd, Schultz, et al, 2008; McBride, Kimpel, McClintick, Ding, Hauser, et al, 2013; McBride, Kimpel, et al, 2014; McBride, Rodd, et al, 2014; Murphy et al, 2002). Ethanol-drinking in the home-cage also results in intoxication including motor impairment, as measured with an oscillating bar apparatus (Bell, McKinzie, Murphy, & McBride, 2000; Bell et al, 2001).…”

“…Ethanol is consumed and self-administered despite ethanol-induced motor impairment (Bell et al, 2011; McBride, Kimpel, McClintick, Ding, Hauser, et al, 2013)…”

“…Additonally, there is higher expression of Chat (choline acetyltransferase), Chrm3 (mACh3R), Slc5a7 (transporter uptake for acetylcholine synthesis), Slc18a3 (vesicular amine transport into secretory vesicles) in the NAcbSh of adult P rats compared with NP rats, whereas adult P rats have lower expression of Chrm4 (mACh4R) in the NAcbSh than NP rats (McBride, Kimpel, McClintick, Ding, Hauser, et al, 2013, McBride, Kimpel, McClintick, Ding, Hyytia, et al, 2013). These findings suggest that the accumbal cholinergic system may be more active in P rats than NP rats.…”

Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

“…Il22ra2 encodes for IL-22 receptor α2 subunit (IL-22ra2; IL-22BP; CFR2–10), which is primarily a pro-inflammatory antagonist of IL-22 activity (Kotenko et al 2001). Similarly, changes in expression of genes associated with cell death have been reported in the NAc shell of P rats following binge-like alcohol drinking (McBride et al 2010, 2013a), and in the VTA of P rats following excessive binge-like alcohol drinking (McBride et al 2013a). These findings may indicate that innate vulnerability to neuroinflammation is exacerbated by excessive ethanol (EtOH) intake, and could contribute to this high alcohol drinking phenotype.…”