Unraveling the Role of Arginine Methyltransferase 1 in Cocaine-Induced Behavioral Alterations

New research indicates that changes in the structure of proteins called histones can influence how cocaine affects the behavior of mice. A specific type of histone modification, involving the addition of methyl groups to arginine, is catalyzed by enzymes known as protein arginine N-methyltransferases (PRMTs). PRMT1, a key enzyme in this process, is responsible for a significant portion of the methylation activity in cells. This enzyme is involved in the methylation of a particular part of histone H4, which is linked to stable changes in gene expression.

Our study has found that giving mice repeated doses of cocaine increases the activity of PRMT1 in a specific region of the brain called the nucleus accumbens. We identified a compound, SKLB-639, which specifically inhibits PRMT1. When this compound was given to mice, it reduced the preference for environments associated with cocaine, similar to the effects seen when PRMT1 is genetically reduced.

Furthermore, we discovered that reducing PRMT1 in the nucleus accumbens leads to changes in the methylation and acetylation of other histones, which are also important for gene regulation. We also observed that a particular methylation pattern of histone H4 is increased after cocaine treatment and that this change influences the expression of two proteins, Cdk5 and CaMKII.

By using a technique to reduce PRMT1 levels in the nucleus accumbens, we showed that this reduction decreases the levels of Cdk5 and CaMKII in mice treated with cocaine. Importantly, the increase in histone methylation caused by repeated cocaine administration lasts for a considerable time, with elevated levels observed up to a week after the last dose of cocaine.

These findings highlight the potential of targeting PRMT1 as a strategy for treating cocaine addiction, suggesting that inhibiting this enzyme could help reduce the behavioral effects associated with cocaine use.