Promising new drug targets for cocaine addiction found

January 20, 2014

Researchers from the Icahn School of Medicine at Mount Sinai have identified a new molecular mechanism by which cocaine alters the brain's reward circuits and causes addiction. Published online in the journal Proceedings of the National Academy of Sciences by Dr. Eric J. Nestler, MD, PhD, and colleagues, the preclinical research 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 , 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," said 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. 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.

Kimberly Scobie, PhD, the lead investigator and postdoctoral fellow in Dr. Nestler's laboratory, underscored the value of implicating PARP-1 in mediating the brain's reward center. "It is striking that changing the level of PARP-1 alone is sufficient to influence the rewarding effects of cocaine," she said.

Next, the investigators used chromatin immunoprecipitation sequencing to identify which genes are altered through the epigenetic changes induced by PARP-1. One target gene whose expression changed after chronic cocaine use was sidekick-1, a cell adhesion molecule concentrated at synapses that directs . Sidekick-1 has not been studied to date in the brain, nor has it been studied in relation to cocaine exposure. Using viral mediated gene transfer to overexpress sidekick-1 in the nucleus accumbens, investigators saw that this overexpression alone not only increased the rewarding effects of cocaine, but it also induced changes in the morphology and synaptic connections of neurons in this brain reward region.

The research opens the door to a brand new direction for therapeutics to treat . Effective drug therapies are urgently needed. National data from the US National Institute of Drug Abuse reveal that nearly 1.4 million Americans meet criteria for dependence or abuse of .

Explore further: Silencing synapses: Hope for a pharmacological solution to cocaine addiction

More information: Essential role of poly(ADP-ribosyl)ation in cocaine action, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1319703111

Related Stories

Silencing synapses: Hope for a pharmacological solution to cocaine addiction

December 17, 2013
Imagine kicking a cocaine addiction by simply popping a pill that alters the way your brain processes chemical addiction. New research from the University of Pittsburgh suggests that a method of biologically manipulating ...

Cocaine decreases activity of a protein necessary for normal functioning of the brain's reward system

April 22, 2012
New research from Mount Sinai Medical Center in New York reveals that repeated exposure to cocaine decreases the activity of a protein necessary for normal functioning of the brain's reward system, thus enhancing the reward ...

Sons of cocaine-using fathers may resist addiction to drug, study suggests

November 11, 2013
A father's cocaine use may make his sons less sensitive to the drug and thereby more likely to resist addictive behaviors, suggests new findings from an animal study presented by Penn Medicine researchers at Neuroscience ...

How the brain puts the brakes on the negative impact of cocaine

January 11, 2012
Research published by Cell Press in the January 12 issue of the journal Neuron provides fascinating insight into a newly discovered brain mechanism that limits the rewarding impact of cocaine. The study describes protective ...

Recommended for you

Zebrafish study reveals clues to healing spinal cord injuries

July 25, 2017
Fresh insights into how zebrafish repair their nerve connections could hold clues to new therapies for people with spinal cord injuries.

Brain stimulation may improve cognitive performance in people with schizophrenia

July 24, 2017
Brain stimulation could be used to treat cognitive deficits frequently associated with schizophrenia, according to a new study from King's College London.

New map may lead to drug development for complex brain disorders, researcher says

July 24, 2017
Just as parents are not the root of all their children's problems, a single gene mutation can't be blamed for complex brain disorders like autism, according to a Keck School of Medicine of USC neuroscientist.

Bird songs provide insight into how developing brain forms memories

July 24, 2017
Researchers at the University of Chicago have demonstrated, for the first time, that a key protein complex in the brain is linked to the ability of young animals to learn behavioral patterns from adults.

Research identifies new brain death pathway in Alzheimer's disease

July 24, 2017
Alzheimer's disease tragically ravages the brains, memories and ultimately, personalities of its victims. Now affecting 5 million Americans, Alzheimer's disease is the sixth leading cause of death in the U.S., and a cure ...

Working around spinal injuries: Rehabilitation, drug treatment lets rats recover some involuntary movement

July 24, 2017
A new study in rats shows that changes in the brain after spinal cord injury are necessary to restore at least some function to lower limbs. The work was published recently in the journal eLife.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.