Transcriptome analysis of frontal cortex in alcohol‐preferring and nonpreferring rats

Abstract

Although it is widely accepted that alcohol abuse and alcoholism have a significant genetic component of risk, the identities of the genes themselves remain obscure. To illuminate such potential genetic contributions, DNA macroarrays were used to probe for differences in normative cortical gene expression between rat strains genetically selected for alcohol self-administration preference, AA (Alko, alcohol) and P (Indiana, preferring), or avoidance, ANA (Alko, nonalcohol) and NP (Indiana, nonpreferring). Among 1,176 genes studied, six demonstrated confirmable, differential expression following comparison of ethanol-naive AA and ANA rats. Specifically, the mRNA level for metabotropic glutamate receptor 3 (mGluR3) was down-regulated in the AA vs. ANA lines. In contrast, calcium channel subunit alpha2delta1 (cacna2d1), vesicle-associated membrane protein 2 (VAMP2), syntaxin 1 (both syntaxin 1a and 1b; STX1a and STX1b), and syntaxin binding protein (MUNC-18) mRNAs were found to be increased in frontal cortex following comparison of AA with ANA animals. Bioinformatic analysis of these molecular targets showed that mGluR3 and cacna2d1 fall within chromosomal locations reported to be alcohol-related by the Collaborative Study on the Genetics of Alcoholism (COGA) as well as quantitative trait loci (QTL) studies. To determine further whether these differences were strain specific, the above-mentioned genes were compared in ethanol-preferring (P) and -nonpreferring (NP) selected lines. VAMP2 was the only gene that displayed statistically different mRNA levels in a comparison of P and NP rats. In conclusion, the altered cortical gene expression illuminated here would have the effect of altering neurotransmitter release in AA rats (compared with ANA rats). Such alterations, however, might not be a universal characteristic of all animal models of alcohol abuse and will also require further investigation in post-mortem human samples.

Glutamate Signaling in Alcohol Abuse and Dependence

“…The seminal paper by Simonyi et al (2000) indicated reductions in the mRNA expression for mGlu3 and mGlu7 receptors within hippocampal subregions, but no changes in mGlu8 mRNA levels, in rats with a chronic history of ethanol intake. Consistent with these data, alcohol-naïve, alcohol-preferring AA (Alko, alcohol) rats exhibit downregulated mRNA expression for the mGlu3 receptor within the cortex relative to alcohol nonpreferring ANA (Alko, nonalcohol) rats, when assayed by gene array (Worst et al, 2005), suggesting cortical mGlu3 receptor expression as a potential biochemical correlate of genetic vulnerability to consume alcohol. In contrast to the aforementioned reports, the increased [ 35 S]GTPγS binding elicited by the mGlu2/3 agonist LY379268 was found to be significantly augmented within both the CeA and the bed nucleus of the stria terminalis in alcoholdependent rats regardless of their withdrawal history (i.e., single versus multiple withdrawals; Kufahl, MartinFardon, & Weiss, 2011).…”

Functional gene expression differences between inbred alcohol-preferring and –non-preferring rats in five brain regions

“…Genes involved in cell growth and adhesion, cellular stress reduction and antioxidation, protein trafficking, cellular signaling pathways, and synaptic function were differentially expressed in the HIPP (Edenberg et al, 2005). Worst et al (2005) reported on the transcriptome analysis in the anterior cerebral cortex of alcohol-naïve Alko, alcohol (AA) and Alko, nonalcohol (ANA) rats, and found differences in mRNA levels between the AA and ANA rats that could alter transmitter release (e.g., vesicleassociated membrane protein 2, syntaxin 1, syntaxin binding protein). Kerns et al (2005) examined gene expression differences in response to acute ethanol in the ACB, prefrontal cortex, and ventral tegmental area of C57BL/6J and DBA/2J mice, which have high and low alcohol drinking characteristics, respectively.…”

Effects of acute ethanol on β-endorphin release in the nucleus accumbens of selectively bred lines of alcohol-preferring AA and alcohol-avoiding ANA rats

“…In this paradigm, the nonselected Wistar rats drink about 2.0 g alcohol/kg/day (Myers 1962), the AA rats drink from 5 to 7 g alcohol/kg/day, while the ANA rats drink less than 1 g alcohol/kg/day (Lê and Kiianmaa 1988;Sinclair et al 1989). Based on this difference in alcohol consumption, these lines of rats have been used in a number of studies investigating the presence of neurobiological differences that could account for their variation in alcohol consumption (Sommer et al 2006;Worst et al 2005). The AA and ANA rats show differences in many neurotransmitter systems, among which is the endogenous opioid system (de Waele et al , 1995Gianoulakis et al 1992;Marinelli et al 2000).…”