Study reveals common brain mechanisms of cocaine and morphine addiction

Researchers at Mount Sinai, in collaboration with scientists at Rockefeller University, have uncovered the mechanisms in the brain that allow cocaine and morphine to take over the natural reward processing system.Published online science April 18, 2020 These findings shed new light on the neural basis of drug addiction and may provide new mechanistic insights that can inform basic research, clinical practice, and potential therapeutic solutions. .

Although this area has been studied for decades, our study is the first to demonstrate that psychostimulants and opioids engage and alter the function of the same brain cells responsible for natural reward processing. did. These findings shed light on how these drugs disrupt normal brain function, how that disruption magnifies with increased drug exposure, and ultimately becomes a hallmark of the pathology of addiction. It provides an explanation for why some people compulsively redirect their behavior toward drugs. ”

Eric J. Nessler, MD, senior author, Nash Family Professor of Neuroscience, director of the Friedman Brain Institute, dean of academic affairs at the Icahn School of Medicine at Mount Sinai, and chief scientific officer of the Mount Sinai Health System

This study focused on identifying convergent mechanisms of addiction in a mouse model across two different classes of drugs: the psychostimulant cocaine and the opioid morphine. This groundbreaking study included Dr. Nessler's longtime collaborator Jeffrey M. Friedman, M.D., Professor Marilyn M. Simpson of Rockefeller University, Howard Hughes Medical Institute Investigator, and the study's co-senior author. The members also included two biophysicists. Alipasha Vaziri, Ph.D., professor of neuroscience and behavior at Rockefeller University and co-senior author of the study, and Tobias Nebauer, Ph.D., assistant professor at Rockefeller University and co-senior author. of research. The team worked closely together to employ a suite of cutting-edge tools and methodologies across behavioral, circuit, cellular, and molecular areas of neuroscience.

Through these innovative efforts, researchers are studying how individual neurons in a forebrain region called the nucleus accumbens respond to natural rewards such as food and water, as well as acute repeated exposure to cocaine and morphine. We were able to track the response in a cell type-specific manner. . They found that the populations of cells that respond to both addictive drugs and natural rewards are nearly overlapping, and that repeated exposure to drugs gradually destroys the cells' ability to function normally, resulting in , demonstrated that behavior is directed toward drug seeking and away from natural rewards. .

“By tracking these cells, we found that not only are similar cells activated across reward classes, but that cocaine and morphine initially elicit a stronger response than food or water, and that as exposure increases, this actually increases. “We also showed an increased response,” said co-author Caleb Brown. , Ph.D., a former instructor in Dr. Nessler's lab and currently a scientist at the Campbell Family Mental Health Institute at the Center for Addiction and Mental Health (CAMH) in Toronto. “After drug withdrawal, these same cells respond disorganized to natural rewards in a way that resembles some of the negative emotional states seen during withdrawal from substance use disorders.”

Additionally, the research team identified a well-established intracellular signaling pathway – mTORC1 – that facilitates the disruption of natural reward processing by drugs. As part of that discovery, researchers discovered the gene (Rev), which encodes an activator of the mTORC1 pathway that may mediate this relationship, potentially providing novel therapeutic targets for future discovery in a medical field where there are currently few effective treatments. There is sex.

To achieve this goal, the research team will delve deeper into the cell biology behind addiction neuroscience to better uncover molecular pathways that may be important for basic research and, ultimately, clinical practice. We are planning to characterize it as follows.

“Through our research, we also established a groundbreaking dataset that integrates drug-induced brain-wide neural activation and input circuit mapping from the nucleus accumbens. “This could be useful for the broader scientific community,” said Bowen-Tan. He is the study's other co-lead author and a graduate student in Dr. Friedman's lab.

“We've known for decades that natural rewards, such as food or addictive drugs, can activate the same areas of the brain,” says Dr. Friedman. “But what we've now learned is that they affect neural activity in strikingly different ways. One of the big takeaways here is that addictive drugs cause pathology in these neural pathways. It has a different physiological effect than, say, when you take a drug.'' Eat when you're hungry and drink a glass of water when you're thirsty. ”

“A large part of our ongoing research focuses on how multimodal information flows are incorporated into brain cell value calculations, and how these key mechanisms influence how drugs respond to natural rewards. “It will be aimed at defining whether it overtakes processing and leads to addiction,” he says. Nessler.