Research identified a brain mechanism through which cocaine and morphine disrupt natural reward processing systems.
According to Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, the study is the first to reveal that psychostimulants and opioids influence the same brain cells involved in natural reward processing. Dr. Nestler emphasized that the findings offer an explanation for the way these substances disrupt normal brain function and amplify this interference over time, leading to compulsive behavior directed toward drug use—a defining characteristic of addiction.
The investigation centered on shared addiction mechanisms in mouse models involving two distinct drug classes: cocaine and morphine. The interdisciplinary effort was led by Dr. Nestler alongside Jeffrey M. Friedman, MD, PhD, of The Rockefeller University, an investigator at the Howard Hughes Medical Institute and co-senior author of the study.
Among the contributors were two biophysicists: Alipasha Vaziri, PhD, Professor of Neuroscience and Behavior at The Rockefeller University, and Tobias Nöbauer, PhD, Assistant Research Professor at the same institution. Both played pivotal roles in employing advanced tools and methodologies that spanned behavioral, circuit, cellular, and molecular neuroscience domains.
Innovative techniques allowed the tracking of individual neurons in the nucleus accumbens, a forebrain region linked to reward processing. Responses to natural rewards, such as food and water, were analyzed alongside reactions to both acute and repeated exposure to cocaine and morphine, with a focus on specific cell types.
Findings revealed that the same group of neurons responds to both addictive substances and natural rewards. Repeated exposure to the drugs was shown to disrupt the normal functioning of these cells, leading to a shift in behavior toward drug-seeking and away from natural reward-seeking.
“Tracking these cells has shown that similar neurons are activated across different reward types, with cocaine and morphine initially eliciting stronger responses than food or water. After drug withdrawal, these neurons display disorganized responses to natural rewards, potentially reflecting negative affective states associated with withdrawal in substance use disorders.”
– Caleb Browne, PhD
The research identified the mTORC1 intracellular signaling pathway as a key mechanism through which drugs disrupt natural reward processing. A gene called Rheb, which activates the mTORC1 pathway, was highlighted as a potential therapeutic target for future advancements in a field with limited effective treatment options.
Further investigations are planned to explore the cellular biology underlying addiction neuroscience, with the goal of uncovering molecular pathways that could inform both foundational research and clinical applications.
“Through this work, a comprehensive dataset has been established, integrating drug-induced brain-wide neural activation with input circuit mapping from the nucleus accumbens. This dataset could provide valuable insights for the broader scientific community engaged in substance use disorder research.”
– Bowen Tan
“It has been understood for decades that natural rewards such as food and addictive substances activate the same brain region. However, recent findings reveal that these influences on neural activity differ significantly. Addictive drugs exert pathological effects on neural pathways that differ markedly from the physiological responses triggered by hunger or thirst.”
– Jeffrey M. Friedman
Ongoing research efforts will focus on understanding how multimodal information is integrated into value computations by brain cells. This mechanism is considered critical for understanding how drugs overpower the processing of natural rewards, ultimately driving addiction, as emphasized by Dr. Nestler.
https://dx.doi.org/10.1126/science.adk6742
Abstract
Drugs of abuse are thought to promote addiction in part by “hijacking” brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell type–specific manner. Combining FOS-Seq, CRISPR-perturbation, and single-nucleus RNA sequencing, we identified Rheb as a molecular substrate that regulates cell type–specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic, molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.
