Researchers at Karolinska Institutet, Columbia University and the University of San Francisco, have uncovered a previously unknown mechanism by which dopamine, a key brain chemical vital for movement and motivation, can affect brain activity indirectly, by boosting serotonin. The study was recently published in Sciences Advances.
Dopamine is a key chemical messenger that supports many essential brain functions, including motivation, movement, and learning. Although dopamine acts throughout the brain, it plays an especially central role in the basal ganglia, a network of interconnected regions responsible for selecting which behaviours we express. The basal ganglia and dopamine are deeply involved in neuropsychiatric and neurodegenerative diseases, and many widely used medications target this network.
Despite its broad importance, dopamine is produced by only a small population of neurons located deep in the brain. These cells send extensive projections that distribute dopamine widely. Curiously, dopamine neurons also release dopamine locally, particularly within a region called the substantia nigra pars reticulata (SNr), around their own cell bodies. The function of this locally released dopamine has remained unknown.
"Rather than examining dopamine's effects at distant targets, we set out to understand how dopamine released within the SNr itself influences basal ganglia function," says Anders Borgkvist , researcher at the Department of Neuroscience and last author of the study.
Indirect and unrecognised mechanism
The results are important because they reveal a previously unknown way in which brain chemicals can influence one another.
"For the first time, we have identified a mechanism through which dopamine can exert indirect effects by acting through serotonin. This kind of neurotransmitter "crosstalk" suggests that similar interactions may be more widespread than previously thought," says Maya Molinari , doctoral student at the same department and first author of the study.
Dopamine and serotonin regulate motivation and mood. The study indicates a regional and synaptic link between these two important functions.
"Ultimately, understanding these chemical relationships can deepen our understanding of neurological disorders affecting movement, motivation, or both," Maya Molinari continues.
A combination of advanced techniques
The team used a combination of advanced techniques, including two-photon imaging to monitor serotonin in real time and optogenetics to control specific neurons with light. These methods allowed them to map how dopamine indirectly influences basal ganglia output.
The team measured SNr neuron activity and GABA release, using drugs targeting dopamine and serotonin receptors to reveal how dopamine indirectly regulates GABA release via serotonin and to examine interactions between these neurotransmitters.
The next step
The aim is to determine if dopamine-serotonin interactions affect disease states like Parkinson's, where dopamine cell loss disrupts basal ganglia circuits.
"We will assess whether altering this interaction improves circuit function or motor symptoms. Additionally, we will investigate if similar pathways occur in other brain regions linked to motivation, reward, and mood, which may expand clinical relevance," says Anders Borgkvist.
Publication
Molinari M, Aaltonen A, Lieberman OJ, Sulzer D, Santini E, Borgkvist A
Sci Adv 2025 Nov;11(45):eadx4577
