Icahn School of Medicine at Mount Sinai researchers have discovered a new molecular mechanism through which cocaine alters the brain's reward circuits and causes addiction.
The preclinical research by Dr. Eric J. Nestler, MD, PhD, and colleagues reveals 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 "mark" activates or represses certain genes encoding synaptic proteins within the DNA.
The marks indicate epigenetic changes-changes made by enzymes-that 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.
"This discovery provides new leads for the development of anti-addiction medications," the study's senior author, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute, at the Icahn School of Medicine at Mount Sinai, said.
Dr. Nestler said 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.
The study is published online in the journal Proceedings of the National Academy of Sciences.