The current opioid epidemic necessitates a better understanding of human addiction
neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide
assessment of chromatin accessibility of the human striatum in heroin users and matched
controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures,
and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as
the most affected region in neurons. FYN expression, kinase activity and the phosphorylation
of its target Tau are increased by heroin use in the post-mortem human striatum, as
well as in rats trained to self-administer heroin and primary striatal neurons treated
with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity
significantly attenuates heroin self-administration and responding for drug-paired
cues in rodents. Our findings suggest that striatal FYN is an important driver of
heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN
a promising therapeutic target for heroin use disorder.