• Press Release

Cocaine Use Alters Gene Expression in Brain Reward Circuits

Mount Sinai researchers investigate transcriptome-wide alterations in response to cocaine self-administration in mice

  • New York, NY
  • (May 31, 2018)

Unique genetic changes in the brain’s reward circuitry are associated with cocaine use, including first-time use, withdrawal, and re-exposure to the drug after prolonged withdrawal, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published Thursday, May 31, in the journal Biological Psychiatry.  The findings reveal important information on how cocaine addiction reprograms gene expression and provides a look into the molecular basis of cocaine addiction in unprecedented detail.

In the study, mice were allowed to self-administer cocaine as a model of human addiction, and the gene expression changes were associated with their addiction-like behavior.  Mount Sinai researchers examined six regions composing the brain’s reward circuitry, providing an enormous resource of information for studying the biological basis of cocaine addiction.

“This study is the first of its kind to characterize the complete genome-wide map of gene expression or RNA expression in the brain during the life-cycle of cocaine self-administration,” said 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.

To characterize the entire life-cycle, Dr. Nestler and colleagues identified differences in gene expression when mice were first exposed to cocaine, in cocaine-addicted mice after a short (24 hours) or long (30 days) period of withdrawal from the drug, and when addicted mice were re-exposed to cocaine after the 30-day withdrawal.  Gene expression was determined by performing RNA-sequencing on six brain regions isolated from mice under these different conditions. This experimental design allowed the research team to study how gene expression across brain reward regions changes over time as a result of volitional cocaine intake.

Previous studies have been limited—focusing either on specific genes, a particular brain region, or one aspect of cocaine addiction—and molecular studies aimed at improving addiction treatment have been complicated by alterations in genes that differ throughout the brain, increasing in some regions and decreasing in others.

The new analysis revealed changes in many genes involved in key biological processes, providing clues into the brain functions that might lead to cocaine addiction.  Many changes were in the same direction (increased or decreased) throughout the reward circuitry, suggesting they may be good targets for new treatments.  Interestingly, the size of the changes depended on the condition—where the mice were in the life-cycle of cocaine self-administration—highlighting unique gene changes associated with the different stages of drug-taking.  The study also identified several molecules responsible for regulating the expression of genes associated with addiction-like behavior.

“This study elegantly highlights the complexity of the brain’s molecular response to self-administered cocaine, pointing to mechanisms that might be targeted by treatments,” said John Krystal, Editor of Biological Psychiatry.

About the Mount Sinai Health System

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.

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