A recent study has identified the brain pathways that addictive drugs such as morphine and cocaine manipulate, which may explain how these substances can override natural needs like eating and drinking. The findings, published in the journal Science, reveal that while drugs of abuse activate the same brain areas as natural rewards such as food and water, they do so in significantly different ways, potentially offering new insights into the treatment of addiction in humans.
Previous research on addiction has consistently shown that both natural rewards (such as food and water) and drugs of abuse (like cocaine and morphine) stimulate the same brain regions, particularly the nucleus accumbens, which is central to the brain’s reward system. This overlap suggests that addictive substances might exploit these natural pathways to exert their effects, leading to the addictive behaviors observed in humans and other animals.
While previous studies had established a general understanding that drugs could hijack the brain’s reward system, they left gaps in our knowledge about the specific neural circuits and cellular responses involved. Specifically, earlier research had not definitively identified which neurons in the nucleus accumbens were being affected by drugs versus those activated by natural rewards.
“It has long been stated that drugs of abuse ‘hijack’ the brain’s reward circuitry that evolved to mediate responses to and consumption of natural rewards,” explained senior author Eric J. Nestler, the Nash Family Professor of Neuroscience, director of The Friedman Brain Institute, and dean for academic affairs of the Icahn School of Medicine at Mount Sinai, and chief scientific officer of the Mount Sinai Health System.
“However, neural substrates for this drug action have not previously been demonstrated. Having recently characterized neural substrates in nucleus accumbens for food in a fasting animal and for water in a thirsty animal provided the perfect opportunity for us to address this gap in the field.”
The researchers used a blend of genetic, imaging, and behavioral techniques to investigate how two drugs of abuse — cocaine and morphine — affect the brain’s reward system compared to natural rewards. Adult male mice were used as the experimental subjects, subjected to conditions like fasting and dehydration to mimic natural states of need.
The researchers demonstrated that both cocaine and morphine significantly reduced food and water intake in mice. This effect was most pronounced following repeated exposure, indicating that the drugs not only trigger an initial decrease in natural reward consumption but also lead to a sustained suppression over time.
These findings were consistent with the hypothesis that addictive drugs hijack the brain’s natural reward pathways, redirecting them towards drug-seeking and drug-taking behaviors at the expense of other biological needs.
Through detailed brain mapping, the researchers identified specific regions within the nucleus accumbens that responded robustly to both types of rewards but in different ways. While natural rewards activated these regions in a manner consistent with normal physiological needs, drugs like cocaine and morphine triggered more intense and distinct patterns of neural activity.
Interestingly, cocaine was found to predominantly activate a subset of neurons, while morphine influenced a broader range of neuronal responses. This suggests that while overlapping neural circuits may be involved in the processing of both drug-related and natural rewards, the actual neural engagement by these substances is unique and distinct.
“Though both drugs and natural rewards activate an overlapping set of medium spiney neurons, cocaine and morphine each activate distinct cell types,” explained Bowen Tan, co-first author of the study and a graduate student at The Rockefeller University. “Their distinct actions within the NAc underscore how the diverse neural dynamics elicited by drugs ultimately shape the different behavioral and physiological outcomes observed in regard to natural rewards.”
“We were surprised that drugs of abuse activate such a large percentage of nucleus accumbens neurons because earlier studies that addressed this question using drug activation of molecular transgenes in mutant mice and rats found drug activation of only small subsets of nucleus accumbens neurons,” Nestler said. “Our experimental approach is thus far more sensitive and complete in capturing drug-regulated nerve cells.”
Moreover, using chemogenetic tools, which allow for the manipulation of neuron activity through designer receptors exclusively activated by designer drugs (DREADDs), the researchers could selectively inhibit these drug-activated neural pathways. They found that doing so prevented the usual drug-induced reductions in food and water intake.
For a closer look at the dynamics of neuron activity at the cellular level, the researchers utilized two-photon calcium imaging. This approach revealed that the drug-induced changes in neural activity were not only different in magnitude but also in the pattern compared to those induced by natural rewards. For instance, neurons that responded to natural rewards did so at a consistent baseline level that did not change significantly with repeated exposure. In contrast, neurons activated by drugs showed altered response patterns that intensified with repeated use, a hallmark of addictive processes.
“By tracking these cells, we show that not only are similar cells activated across reward classes, but also that cocaine and morphine elicit initially stronger responses than food or water, and this actually magnifies with increasing exposure,” said co-first author Caleb Browne,a former Instructor in Dr. Nestler’s lab who is now a Scientist in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health. “After withdrawal from the drugs, these same cells exhibit disorganized responses to natural rewards in a manner that may resemble some of the negative affective states seen in withdrawal in substance use disorder.”
“The major finding is that initial exposure to cocaine or to morphine, representing two major classes of drugs of abuse, activates many of the same neurons that are activated by food in a fasting animal and by water in a thirsty animal, but that with repeated exposure both drugs produce increasingly potent responses while disrupting responses to natural rewards,” Nestler told PsyPost. “These findings provide a mechanism by which the drugs corrupt the brain’s reward circuitry and increase motivation for the drugs while reducing it for healthy rewards.”
“We’ve known for decades that natural rewards, like food, and addictive drugs can activate the same brain region,” added Jeffrey M. Friedman, the Marilyn M. Simpson Professor at The Rockefeller University, investigator at the Howard Hughes Medical Institute, and co-senior author of the study. “But what we’ve just learned is that they impact neural activity in strikingly different ways. One of the big takeways here is that addictive drugs have pathologic effects on these neural pathways, that are distinct from, say, the physiologic response to eating a meal when you are hungry or drinking a glass of water when you are thirsty.”
The researchers also shed light on the molecular dynamics within the nucleus accumbens neurons, revealing how exposure to drugs like cocaine and morphine triggers specific genetic changes. They pinpointed a critical intracellular signaling pathway, mTORC1, that drugs manipulate to disrupt natural reward processing and identified a specific gene, Rheb, which activates this pathway.
This finding highlights a potential target for therapeutic intervention. Moving forward, the research team plans to further explore the cellular and molecular mechanisms of addiction, aiming to uncover more about the pivotal pathways involved and how they could be manipulated to develop more effective treatments in addiction medicine — a field where options are currently limited.
“Through our work we have also established a landmark dataset that integrates drug-induced brain-wide neural activation with input circuit mapping from the nucleus accumbens, which could be useful to the broad scientific community conducting substance use disorder research,” Tan said.
“A major part of our ongoing research will be directed to defining how the flow of multimodal information is incorporated into value computations in brain cells and how that crucial mechanism enables drugs to overtake the processing of natural rewards, leading to addiction,” Nestler explained.
“We would love to understand the mechanisms by which cocaine and morphine each activate a partly shared but also partly distinct subpopulation of nucleus accumbens neurons and how those differences underscore distinct features of addiction syndromes seen with these two classes of drugs.”
Nestler added that “it was a special treat to work with two leading scientists at Rockefeller University. Each of us, along with our labs, brought unique expertise to the study with the result being an unusual synthesis of approaches with powerful insights resulting.”
The study, “Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need,” was authored by Bowen Tan, Caleb J. Browne, Tobias Nöbauer, Alipasha Vaziri, Jeffrey M. Friedman, and Eric J. Nestler.
