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.