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

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 Camk2a gene showed a downregulated profile only in the Inflexible when compared to the Light drinkers group, the Camk2n1 and Pkp2 genes showed an upregulated profile only in the Inflexible drinkers when compared to the Control group, and the Gja1 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 Camk2n1 and Gja1 genes; to the amount of ethanol consumed, in the Camk2a gene; and to the loss of control in the alcohol consumption, in the Pkp2 gene. Here, we provide, for the first time, the potential involvement of the Pkp2 gene in the compulsivity and loss of control over the voluntary ethanol consumption.

Inflexible ethanol intake: A putative link with the Lrrk2 pathway.

Alcoholism is a complex multifactorial disorder with a strong genetic influence. Although several studies have shown the impact of high ethanol intake on the striatal gene expression, few have addressed the relationship between the patterns of gene expression underlying the compulsive behaviour associated with the two major concerns in addiction: the excessive drug consumption and relapsing. In this study, we used a chronic three-bottle free-choice murine model to address striatal transcript regulation among animals with different ethanol intakes and preferences: Light Drinkers (preference for water throughout the experiment), Heavy Drinkers (preference for ethanol with a non-compulsive intake) and Inflexible Drinkers (preference for ethanol and simultaneous loss of control over the drug intake). Our aim was to correlate the intake patterns observed in this model with gene expression changes in the striatum, a brain region critical for the development of alcohol addiction. We found that the transcripts of the Lrrk2 gene, which encodes a multifunctional protein with kinase and GTPase activities, is upregulated only in Inflexible Drinkers suggesting, for the first time, that the Lrrk2 pathway plays a major role in the compulsive ethanol intake behaviour of addicted subjects.