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UrduUNDER EMBARGO UNTIL Friday, February 10 at 2:00 PM EST
These changes, which contribute importantly to the persistent behavioral abnormalities seen in addiction to drugs, occur because cocaine use sets off a series of chemical reactions that lead to increases in the amount of messenger RNA being produced from some of the affected genes in these two brain regions, whereas the activity of other genes decreases. Changes in the amount of messenger RNA produced—a process also known as “expression” of the underlying genes—lead to changes in the amount of proteins that are produced and that subsequently carry out chemical reactions in the brain. The research team found a significant overlap between the RNAs expressed in these two brain regions, suggesting that these molecular changes may be key to the development and maintenance of cocaine use disorder.
Cocaine use disorder is a chronic, relapsing brain disorder for which there are currently no FDA-approved medication treatments. While it is hypothesized that regulation of gene expression in the brain’s reward and motivational centers plays a critical role in the persistent behavioral changes that define addiction, knowledge remains limited of the maladaptive gene activity that chronic cocaine use causes in these circuits in humans and that underlies cocaine use disorder.
To address the knowledge gap, the research team performed RNA sequencing in both the nucleus accumbens and caudate nucleus from the postmortem brain tissue of persons with cocaine use disorder and matched controls. Using the largest and most diverse cohort examined to date, they found that neuroinflammatory processes are suppressed and that synaptic transmembrane transporters and ionotropic receptors – proteins that control how nerve cells communicate with one another in the brain—are enriched in the striatum of people with cocaine use disorder.
Cocaine increases the amount of the neurotransmitter dopamine at synapses, or junctions between two brain cells where electrical signals are converted into chemical signals. By doing so, the research team found, cocaine sets off a cascade of events that activate a chemical messenger in the brain called cyclic AMP, which then triggers changes in gene expression.
“In addition to the new insights into the molecular changes that cocaine use confers, we found that people with cocaine use disorder have dysregulated genes associated with schizophrenia and major depressive disorder, which indicates that these disorders may share some underlying gene regulatory and neural circuit systems,” said Philipp Mews, PhD, Instructor of Neuroscience at Icahn Mount Sinai and first author of the paper together with Ashley M. Cunningham, a neuroscience PhD student. “Importantly, the transcriptional abnormalities—in particular, the neuroinflammatory responses that are suppressed in the nucleus accumbens of people with cocaine use disorder—are directionally opposite of the proinflammatory cascade responses conferred by opioid use disorder. The observation that there are distinct molecular changes conferred by each of the two substance use disorders could be valuable for the development of targeted, effective treatments specific to cocaine use disorder.”
Because it is difficult to directly study how drugs like cocaine affect the human brain, researchers often use animal models to study their effects. However, a key question is whether what they learn from these animal models is similar to what happens in the brains of humans who use cocaine.
“Our research team looked at studies performed in mice that were given the opportunity to self-administer cocaine and compared the resulting molecular changes to those seen in postmortem brain tissue of people with cocaine use disorder. Our analysis revealed strikingly similar changes in the brain’s gene expression profiles in both the mice and humans, validating the use of mouse models to study the pathophysiological basis of cocaine use disorder,” said Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, Dean for Academic Affairs at Icahn Mount Sinai, Chief Scientific Officer of the Mount Sinai Health System, and senior author of the paper. “It is also important to emphasize that our human brain cohort includes a significant number of Black individuals, who have not been well represented in prior transcriptional studies of cocaine use disorder, despite longstanding evidence that the highest rate of overdose deaths involving cocaine is among Black individuals. Together, these findings represent a considerable advance in our understanding of the molecular abnormalities in cocaine use disorder and provide a highly valuable resource for future investigations.”
This study was funded by the National Institutes of Health, National Institute on Drug Abuse (P01DA047233, R01DA033684), the National Institute on Alcohol Abuse and Alcoholism (K99AA027839), and the Brain and Behavior Research Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
Ranked No. 14 nationwide in National Institutes of Health funding and in the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators, and clinicians work within and across 34 academic departments and 44 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, and gastrointestinal and liver diseases.
Icahn Mount Sinai offers highly competitive MD, PhD, and master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. In addition, more than 535 postdoctoral research fellows are in training within the Health System.
A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into health care products and services that benefit the public.
Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.
The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem, and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
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