Inhibition of striatal SEZ6 by miR-3594-5p is a drug-specific marker for late-stage heroin intake escalation

SUMMARY Escalation of drug use is a hallmark stage in the transition to addiction and uncovering its underlying brain molecular mechanisms constitutes a considerable challenge. Here, we report in rats with extended access to heroin for self-administration that miR-3594-5p was upregulated in the dorsal striatum at late, but not early, stages during escalation when excessive heroin intake plateaued. Striatal miR-3594-5p bound directly to the 3’UTR region of Sez6 transcript and inhibited its expression, thereby decreasing the mature form of the translated SEZ6 protein. This miR-3594-5p/ Sez6 interaction was specific to heroin, as it was not observed with cocaine, and correlated with the severity of heroin intake escalation. Our findings reveal that miRNA alterations during escalation of drug self-administration are spatially and temporally regulated and drug-specific.