Loss of control over the ethanol consumption: differential transcriptional regulation in prefrontal cortex

<p>Alcohol use disorder (AUD) is a complex multifactorial disease with heritability of ∼50% and corresponds to the state in which the body triggers a reinforcement or reward compulsive behavior due to ethanol consumption, even when faced with negative consequences. Although several studies have shown the impact of high ethanol intake on the prefrontal cortex (PFC) gene expression, few have addressed the relationship between the patterns of gene expression underlying the compulsive behaviour associated with relapsing. In this study, we used a chronic three-bottle free-choice mouse model to investigate the PFC transcriptome in three different groups of mice drinkers: ‘Light drinkers’ (preference for water throughout the experiment); ‘Heavy drinkers’ (preference for ethanol with a non-compulsive intake), and ‘Inflexible drinkers’ (preference for ethanol with a compulsive drinking component). Our aim was to correlate the intake patterns observed in this model with gene expression changes in the PFC, a brain region critical for the development and maintenance of alcohol addiction. We found that the <i>Camk2a</i> gene showed a downregulated profile only in the Inflexible when compared to the Light drinkers group, the <i>Camk2n1</i> and <i>Pkp2</i> genes showed an upregulated profile only in the Inflexible drinkers when compared to the Control group, and the <i>Gja1</i> gene showed an upregulated profile in the Light and Inflexible drinkers when compared to the Control group. These different transcription patterns have been associated to the presence of alcohol, in the <i>Camk2n1</i> and <i>Gja1</i> genes; to the amount of ethanol consumed, in the <i>Camk2a</i> gene; and to the loss of control in the alcohol consumption, in the <i>Pkp2</i> gene. Here, we provide, for the first time, the potential involvement of the <i>Pkp2</i> gene in the compulsivity and loss of control over the voluntary ethanol consumption.</p>