Cocaine Use Alters Gene Expression in Brain Reward Circuits

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Cocaine Use Alters Gene Expression in Brain Reward Circuits
Mount Sinai researchers investigate transcriptome-wide alterations in response to cocaine self-administration in mice

Newswise — (NEW YORK, May 31) 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.

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The Mount Sinai Health System is New York City’s largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai’s vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 7,100 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report’s “Best Medical Schools”, aligned with a U.S. News & World Report’s “Honor Roll” Hospital, No. 13 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report’s “Honor Roll” of top U.S. hospitals; it is one of the nation’s top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in four other specialties in the 2017-2018 “Best Hospitals” issue. Mount Sinai’s Kravis Children’s Hospital also is ranked in six out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and 50th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke’s and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.

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