Scientists from the Icahn School of Medicine at Mount Sinai say they have identified a new molecular mechanism by which cocaine alters the brain's reward circuits and causes addiction. They published their study, “Essential role of poly(ADP-ribosyl)ation in cocaine action,” in the Proceedings of the National Academy of Sciences.
The researchers say their preclinical research shows how an abundant enzyme and synaptic gene affect a key reward circuit in the brain, changing the ways genes are expressed in the nucleus accumbens. The DNA itself does not change, but its epigenetic mark activates or represses certain genes encoding synaptic proteins within the DNA. These epigenetic changes alter the activity of the nucleus accumbens.
In a mouse model, the research team found that chronic cocaine administration increased levels of an enzyme called PARP-1 or poly(ADP-ribosyl)ation polymerase-1. This increase in PARP-1 leads to an increase in its PAR marks at genes in the nucleus accumbens, contributing to long-term cocaine addiction. Although this is the first time PARP-1 has been linked to cocaine addiction, PARP-1 has been under investigation for cancer treatment.
“Specifically, we identified sidekick-1—important for synaptic connections during development—as a critical PARP-1 target gene involved in cocaine’s behavioral effects as well as in its ability to induce dendritic spines on NAc neurons,” wrote the investigators. “These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine.”
“This discovery provides new leads for the development of anti-addiction medications,” said the study's senior author, Eric Nestler, M.D., Ph.D., Nash Family Professor of Neuroscience and director of the Friedman Brain Institute, at the Icahn School of Medicine at Mount Sinai.
Dr. Nestler noted that the research team is using PARP to identify other proteins regulated by cocaine. PARP inhibitors may also prove valuable in changing cocaine's addictive power, he added.