Identification of genes regulated by trait sensitivity to negative feedback and prolonged alcohol consumption in rats

Background: The results of our previous studies demonstrated that low sensitivity to negative feedback (NF) is associated with increased vulnerability to the development of compulsive alcohol-seeking in rats. In the present study, we investigated the molecular underpinnings of this relationship.

Methods: Using TaqMan Gene Expression Array Cards, we analyzed the expression of the genes related to NF sensitivity and alcohol metabolism in three cortical regions (medial prefrontal cortex [mPFC], anterior cingulate cortex [ACC], orbitofrontal cortex [OFC]) and two subcortical regions (nucleus accumbens [Nacc], amygdala [Amy]). Gene expression differences were confirmed at the protein level with Western blot.

Results: Sensitivity to NF was characterized by differences in Gad2, Drd2, and Slc6a4 expression in the ACC, Maoa in the mPFC, and Gria1, Htr3a, and Maoa in the OFC. Chronic alcohol consumption was associated with differences in the expression of Comt and Maoa in the ACC, Comt, Adh1, and Htr2b in the mPFC, Adh1, and Slc6a4 in the Nacc, Gad2, and Htr1a in the OFC, and Drd2 in the Amy. Interactions between the sensitivity to NF and alcohol consumption were observed in the expression of Gabra1, Gabbr2, Grin2a, Grin2b, and Grm3 in the ACC, and Grin2a in the OFC. The observed differences were confirmed at the protein level for MAO-A in the mPFC, and ADH1 in the mPFC and Nacc.

Conclusions: Our findings contribute to a better understanding of the molecular mechanisms underlying the relationship between trait sensitivity to NF and compulsive alcohol consumption.