A recent study from Stanford’s Wu Tsai Neurosciences Institute has shed light on the interplay between two key brain chemicals, dopamine and serotonin, revealing their opposing roles in shaping our decisions and learning processes. Published in Nature, the research demonstrates for the first time that dopamine and serotonin operate as a “gas and brake” system, jointly influencing how we learn from rewards. The findings have broad implications, from understanding everyday decision-making to developing treatments for neurological and psychiatric conditions such as addiction, depression, and Parkinson’s disease.
Dopamine and serotonin are crucial to many aspects of human behavior, including reward processing and decision-making. Both neurotransmitters are also implicated in a variety of mental health disorders. While previous research has established their individual roles—dopamine is linked to reward prediction and seeking, while serotonin promotes long-term thinking and patience—the precise nature of their interaction has remained unclear.
Two competing theories have sought to explain their dynamic: the “synergy hypothesis,” which posits that dopamine focuses on immediate rewards and serotonin on long-term benefits, and the “opponency hypothesis,” suggesting the two act in opposition, with dopamine encouraging impulsive action and serotonin promoting restraint. The Stanford researchers aimed to directly test these theories using advanced experimental methods.
“We’ve known for decades that dopamine and serotonin serve reward-related functions, and that they do so by acting on a common set of target brain regions. This implies that dopamine and serotonin systems work together to drive learning, but exactly how works remained hotly debated in the field,” explained study author Daniel F. Cardozo Pinto (@dcardozopinto), a postdoctoral scholar in the Department of Psychiatry & Behavioral Sciences at Stanford University.
When we kicked off this project around 2018, it was the first time that our genetic tools were advanced enough for us to attempt studying the dopamine and serotonin systems simultaneously. Once we got that to work, we knew we had the right new tool to break open an old and fascinating question.”
The team engineered a group of mice that allowed them to observe and manipulate dopamine and serotonin activity simultaneously. These mice were designed with specialized genetic modifications that enabled researchers to control the neurotransmitters using light, a technique known as optogenetics.
The experiments focused on a brain region called the nucleus accumbens, which is critical for motivation, emotion, and reward processing. Researchers trained the mice to associate specific cues—such as a tone and flashing light—with a sweet reward. During this learning process, the researchers recorded dopamine and serotonin signals and observed how they changed in response to rewards and cues.
They found that dopamine and serotonin activity shifted in opposite directions: dopamine increased with reward signals, while serotonin decreased. This supported the opponency hypothesis, indicating that the two neurotransmitters act as opposing forces during decision-making and learning.
To further test this dynamic, the team used optogenetics to selectively block or restore dopamine and serotonin activity during the learning tasks. Mice were unable to learn reward cues when both dopamine and serotonin signaling were suppressed. Surprisingly, neither neurotransmitter alone was sufficient to restore learning. Only when both systems were active could the mice effectively associate the cues with rewards.
In a related experiment, researchers tested the mice’s preferences for different brain states induced by manipulating dopamine and serotonin. Mice consistently preferred experiences that combined dopamine boosts and serotonin reductions—providing direct behavioral evidence of the opponency model.
“In short, we discovered that dopamine and serotonin signals form a gas-brake system for reward in the mammalian brain,” Cardozo Pinto told PsyPost. “More specifically, we found that when mice consume a sugar reward, dopamine in a key reward center goes up and serotonin goes down. In follow-up experiments, we then showed that artificially recreating both reward signals – a dopamine boost and a serotonin dip – drives reward learning more powerfully than either signal alone. To the best of our knowledge, this study is the first direct demonstration of an opponent relationship between dopamine and serotonin.”
These results have significant implications for understanding disorders that involve dopamine and serotonin dysfunction. For instance, addiction is associated with excessive dopamine activity, leading to compulsive reward-seeking. Depression, meanwhile, is linked to reduced serotonin activity, which may impair behavioral flexibility and long-term planning.
The researchers believe that future treatments for these conditions could target the balance between dopamine and serotonin. For example, therapies for addiction might aim to reduce dopamine activity while enhancing serotonin signaling, while depression treatments might focus on strengthening both systems to restore motivation and decision-making.
While the findings are compelling, the study has limitations. The experiments were conducted in mice, which, though a valuable model for neuroscience, may not fully capture the complexity of human brain function.
Future studies could investigate how these neurotransmitter systems function in different contexts, such as social behavior or stress. The tools developed for this study, which allow precise control and observation of multiple neurotransmitters, could also be applied to other brain chemicals and circuits.
Ultimately, the study underscores the importance of dopamine and serotonin balance in shaping behavior and decision-making. By uncovering how these neurotransmitters work in opposition, researchers have opened new avenues for understanding the brain and addressing the disorders that arise when this balance is disrupted.
“One major goal is to gain a better understanding of the underlying causes of disorders of reward processing – like depression and addiction – and our finding of dopamine and serotonin opponency is exciting because it opens important new research avenues in those fields,” Cardozo Pinto explained. “For example, our work could help explain why drugs that produce both dopamine and serotonin release tend to have lower abuse potential than drugs that primarily release dopamine alone. In general, our work suggests that the relative balance between dopamine and serotonin may play a crucial and previously underappreciated role in the etiology of these disorders.”
The study, “Opponent control of reinforcement by striatal dopamine and serotonin,” was authored by Daniel F. Cardozo Pinto, Matthew B. Pomrenze, Michaela Y. Guo, Gavin C. Touponse, Allen P. F. Chen, Brandon S. Bentzley, Neir Eshel, and Robert C. Malenka.
