Dopamine and serotonin work in opposition to shape learning

Of course, the headlines mostly get it wrong. Dopamine's role in shaping behavior goes way beyond simple concepts like "pleasure" or even "reward." And the fact that it takes weeks or months for serotonin-boosting SSRI antidepressants to work suggests that it's not actually the immediate jump in serotonin levels that drum out the doldrums of depression, but some still-mysterious shift in downstream brain circuits.

A new study from Stanford's Wu Tsai Neurosciences Institute reveals yet another new facet of these mood-managing molecules. The research, published on-line November 25, 2024 in Nature, demonstrates for the first time exactly how dopamine and serotonin work together -- or more precisely, in opposition -- to shape our behavior.

"In addition to their involvement in our everyday behavior, dopamine and serotonin are implicated in a wide variety of neurological and psychiatric disorders: addiction, autism, depression, schizophrenia, Parkinson's and more," said study senior author Robert Malenka, the Pritzker Professor of Psychiatry and Behavioral Sciences at Stanford. "It's critical for us to understand their interactions if we are to make progress treating these disorders."

The theory: dopamine and serotonin are both important for shaping behavior -- but how?

Research has long shown that dopamine and serotonin play crucial roles in learning and decision-making across species. However, the exact interplay between these neurotransmitters has remained unclear. While dopamine is associated with reward prediction and seeking, serotonin seems to moderate these impulses and promote long-term thinking.

Two main theories have emerged: the "synergy hypothesis," which suggests dopamine handles short-term rewards while serotonin manages long-term benefits, and the "opponency hypothesis," which proposes the two act as opposing forces balancing our decisions, with dopamine urging immediate action while serotonin counsels patience.

This new Stanford study, part of Wu Tsai Neuro's NeuroChoice Initiative, provides the first direct experimental test of these competing hypotheses.

The experiment: dual control of dopamine and serotonin during associative learning

Led by graduate student Daniel Cardozo Pinto, the research team created specially engineered mice that allowed them to observe and control both dopamine and serotonin systems in the same animal.

This innovative approach helped them pinpoint where these two systems interact in the brain -- specifically in a limbic region called the nucleus accumbens, which plays a key role in emotion, motivation, and reward processing.

"This was a very technically demanding project that required us to develop new strategies for recording and manipulating the activity of multiple neuromodulators simultaneously in awake, behaving animals," Cardozo Pinto shared. However, he added, "I persevered because I strongly suspected that there would be fascinating interactions between the dopamine and serotonin systems that were being missed by other studies that focused on only one neuromodulator at a time, and it turned out that this was exactly the case."

Cardozo Pinto and colleagues used their innovative new tools to observe how dopamine and serotonin signals changed in the nucleus accumbens as mice learned to connect a tone and flashing light with a sweet reward. They found that the dopamine and serotonin systems responded in opposite directions -- dopamine signaling jumped up in response to the reward, while serotonin signaling fell.

The researchers then used optogenetic manipulation (a technique that uses light to control genetically modified neurons) to selectively blunt the normal signaling of each system -- either alone or in combination -- during reward learning.

Predictably, given the history of studies linking these signaling systems to reward learning, blocking both dopamine and serotonin signaling made it impossible for mice to link sound and light cues with sugary reward. More surprisingly, restoring either dopamine or serotonin signaling on its own was not enough to allow the animals to learn again. Only with both systems online could animals successfully use the cues to predict the arrival of a reward.

"The most surprising and memorable moment in the project came when I performed my first optogenetic experiment, where I tested whether mice preferred the experience of a dopamine boost, a serotonin dip, or both together," Cardozo Pinto recalled. "We placed mice in a box and paired different parts of the box with each of those experiences, so mice could vote with their feet which experience they preferred. I will never forget the thrill of walking into the room at the end of the experiment to see all the mice on the side of the box representing both manipulations together. It's very rare in science to get a result so striking that you can see it immediately, and it was our first direct piece of evidence to support the decades-old hypothesis of dopamine-serotonin opponency."

On the horizon: choreographing dopamine and serotonin to improve psychiatric treatment

The findings suggest that dopamine and serotonin work together, but in opposite ways, to help the brain learn from rewards, the researchers say.

Based on their results, they propose that the two systems act a bit like the accelerator and the brakes on a car. Dopamine encourages reward-seeking behavior by signaling when things are better than expected, creating a 'go' signal. In contrast, serotonin seems to put the brakes on this process, creating a 'stop' or 'wait' signal, potentially helping us to be more patient and consider long-term consequences rather than just immediate rewards. Effective learning, the study suggests, requires both the 'go' signal from dopamine and the 'wait' signal from serotonin for an organism to properly evaluate and respond to rewarding opportunities.

The findings also have implications for disorders involving dopamine and serotonin dysfunction, such as addiction, where dopaminergic hypersensitivity and serotonergic deficits contribute to compulsive reward-seeking -- and in mood disorders including depression and anxiety, where diminished serotonin signaling might impair behavioral flexibility and long-term planning.

"As dopamine's role in reward learning has become increasingly clear, the dopamine system has become a natural place to start for studies investigating diseases that involve disrupted reward processing, like addiction and depression," Cardozo Pinto said. "Our work showing that the dopamine and serotonin systems form a gas-brake system for reward suggests it will be fruitful for future work to focus on the relative balance between these two systems."

For example, in addiction treatment, therapies might aim to dampen overactive dopamine signaling while boosting serotonin activity. In depression, the goal might be to enhance both systems to improve motivation and long-term planning.

Furthermore, the technical advances the team made to accomplish this study, may have long-standing applications for neuroscience research, Malenka added. "The novel methodologies we developed for this study can now be applied to a host of fascinating questions related to how the brain mediates adaptive behaviors and what goes wrong in these neuromodulatory systems during prevalent brain disorders such as addiction, depression, and autism spectrum disorders."

Competing interests: Eshel is a consultant for Boehringer Ingelheim. Bentzley is a co-founder of Magnus Medical. Malenka is on the scientific advisory boards of MapLight Therapeutics, MindMed, and Aelis Farma.