Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.
The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hours after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (p<0.01; Storey false discovery rate=0.15); there were 374 differences in named genes between these 2 groups. There were 20 significant Gene Ontology (GO) categories, which included negative regulation of protein kinase activity, anti-apoptosis, and regulation of G-protein coupled receptor signaling. Ingenuity analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression in the ACB of the CA group), suggesting increased neuronal activity. There were 43 genes located within rat QTLs for alcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal.
Bell
Richard L
RL
Department of Psychiatry, Indiana University Purdue University at Indianapolis, Indianapolis, IN 46202, USA. ribell@iupui.edu
Kimpel
Mark W
MW
McClintick
Jeanette N
JN
Strother
Wendy N
WN
Carr
Lucinda G
LG
Liang
Tiebing
T
Rodd
Zachary A
ZA
Mayfield
R Dayne
RD
Edenberg
Howard J
HJ
McBride
William J
WJ
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D030541:Databases, Genetic; D000431:Ethanol / Q000494:pharmacology*; D005518:Food Preferences; D005786:Gene Expression Regulation / Q000187:drug effects*; D007091:Image Processing, Computer-Assisted; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012646:Self Administration
D002492:Central Nervous System Depressants; D000431:Ethanol; D012313:RNA