Challenging current understanding, the study reveals a rapid release of dopamine that is not necessary to initiate movement

The chemical messenger dopamine is an essential catalyst that fuels activities and behaviors ranging from movement to cognition and learning. However, neuroscientists have long debated whether these functions are based on rapid bursts of dopamine or the neurochemical’s slower action.

A new study led by Harvard Medical School researchers offers an answer.

The work, carried out in mice and published on October 16 a natureshows that the initiation of movement does not require a quick burst of dopamine, but relies on the chemical’s slow activity over time. In contrast, reward-oriented behaviors, related to motivation and learning, rely on the rapid action of dopamine.

“If you read the modern neuroscience of dopamine, one conclusion from this body of literature is that dopamine can act as a fast neurotransmitter to activate and modulate movement, but our study shows that this is not the case,” said the lead study author Pascal Kaeser, professor. in neurobiology at the HMS Blavatnik Institute.

The findings shed light on the molecular mechanism behind the drug levodopa (L-Dopa), widely used to treat Parkinson’s disease. A hallmark of the disease is the progressive depletion of dopamine, which over time leads to tremors and stiffness, as well as a range of cognitive problems, including difficulties with memory, attention, thinking and decision-making.

The study results help explain why L-Dopa generally improves the motor symptoms of Parkinson’s, which do not require a rapid release of dopamine, but is often worse at alleviating cognitive and memory problems, which are often under the control of rapid dopamine signaling.

“Our work is at the heart of L-Dopa’s mechanism of action in locomotion. Our findings confirmed that L-Dopa improves locomotion, but does so without restoring fast dynamics in the model we used.” , said lead study author Xintong Cai. a former HMS Research Fellow in Neurobiology.

Dopamine signaling: fast and slow

Dopamine signaling is a complex, multistep process involving a signal-producing neuron and several signal-receiving cells. It starts when a dopamine-producing neuron is activated by an electrical impulse, which triggers the release of dopamine. Dopamine molecules move out of the cells and bind to receptors on the surface of signal-receiving neurons. This binding initiates a cascade of signaling processes that regulate a wide range of activities and behaviors, from locomotion and reward-seeking to motivation and learning.

In the 1950s, Swedish neuroscientist Arvid Carlsson discovered dopamine as a signaling molecule in the brain. Following this discovery, the prevailing belief in the field was that the neurotransmitter acts slowly over minutes and hours. But over time, Kaeser explained, thinking evolved and neuroscientists moved to a different model. Recent studies have suggested that the neurotransmitter can be released rapidly and precisely on a time scale of milliseconds.

To determine whether behaviors such as learning and movement require the rapid and precise release of dopamine, Kaeser and his team used genetically engineered mice that lacked a protein called RIM, which allows for the rapid action of dopamine in the brain. In fact, when the researchers measured dopamine levels in brain tissue from mice lacking RIM, they found that the rapid and precise release of dopamine was almost completely lacking, compared to mice with intact RIM genes.

The team then conducted a series of behavioral experiments to see how the movement of RIM-deficient mice was affected by the loss of fast dopamine signaling. This involved assessing the animals’ gait and coordination while performing various activities, such as walking through an open area or going down a bar. To the researchers’ surprise, the mice were still able to initiate movement and perform basic tasks, despite the absence of fast dopamine signaling.

The story, however, changed when it came to behaviors related to motivation. Mice lacking fast dopamine signaling learned to associate rewards such as water and food with location and smell, but were less likely to lick the waterspout in anticipation of reward, compared to their peers with intact fast dopamine signaling. The finding clearly suggested a decrease in reward motivation.

The role of dopamine in movement disorders

Dopamine, the main culprit in Parkinson’s, has long been the main treatment target for this neurodegenerative disease, which is characterized by the gradual disappearance of dopamine-producing neurons.

L-Dopa, a commonly used therapy for Parkinson’s, is effective in improving movement symptoms, although it is not yet clear whether the drug restores dopamine dynamics in the brain.

To unravel the mechanism underlying L-Dopa’s effects, researchers gave the drug to dopamine-deficient mice with an impaired ability to initiate movement, similar to symptoms seen in Parkinson’s patients. The researchers also measured the release of dopamine in the animals’ brains after the injection. Mice treated with L-Dopa regained movement, but the drug did not restore rapid dopamine signaling in the brain.

Together, these findings, Kaeser says, help explain how L-Dopa improves movement-related symptoms in Parkinson’s and may also explain why it is less effective in treating cognitive problems, such as those related to learning. and motivation, two activities that depend on the fast. release of dopamine.

“Sooner or later, most Parkinson’s patients get L-Dopa,” he added. “Hopefully, our findings will help researchers think about how they might ameliorate the cognitive problems seen in this disease by developing therapies that lead to faster and more accurate dopamine signaling.”