The Wonders Of Neurotransmitters:
Dopamine

Dopamine is a neurotransmitter, a chemical substance used for communication between neurons. Our brain consists of numerous densely packed nerve cells, but not all of them communicate with one another. For a connection to exist between two cells, a one-way neural junction - known as a synapse - must form between them. Synapses are narrow spaces between the cells into which one nerve cell releases a neurotransmitter and another nerve cell receives the substance through dedicated receptors, responding accordingly. While the number of neurons that produce and release dopamine is not high, and they are concentrated in very specific regions in the brain, the released dopamine reaches extensive parts of the central nervous system, influencing a wide range of conditions and behaviors.

Dopamine belongs to the group of monoamines, chemically related to the hormone adrenaline and the neurotransmitter serotonin. These are all small molecules produced from a single amino acid that undergoes chemical modifications. Amino acids are better known as the building blocks of proteins in our body, but in this case,  they serve as messengers mediating communication between nerve cells. The use of dopamine as a neurotransmitter began very early in evolution and is present in all animals with a nervous system.

A chemical substance used for communication between nerve cells. Structure of a dopamine molecule | Kateryna Kon, Shutterstock

Mechanism of Action

Dopamine is classified as a modulatory neurotransmitter, because its effect on nerve cells depends on the type of receptors the cell has. Dopamine interacts with five different receptors, divided into two groups. The first group, called D1 receptors, are considered excitatory, meaning they tend to increase the activity rate of their nerve cell. In contrast, D2 receptors are considered inhibitory, meaning they reduce the cell’s activity rate. 

This begs the question of how do cells decide which receptor type to activate? Dopamine-producing nerve cells typically release small, constant amounts of dopamine, which is primarily intercepted by the highly sensitive D2 receptors—up to 100 times more sensitive than D1 receptors. As a result, the activity of the receiving cells remains low most of the time. However, under certain conditions, dopamine cells suddenly release large amounts of dopamine at a rapid pace. This activates the D1 receptors, increasing the nerve cell’s activity rate. 

This mechanism has an additional layer of sophistication. The amount of dopamine in the vicinity of the receptors is determined not only by the release rate of the neurotransmitter but also by the rate at which it is cleared from the synaptic cleft - the space within the synapse. Dopamine-producing nerve cells have tiny channels in their membranes that reabsorb dopamine back into the cell, reducing the amount of dopamine in the synapse. This means less dopamine is available to bind to receptors and modulate neural activity.

Interestingly, dopamine appears to function both within synapses and outside them. Detailed brain studies have shown that dopamine receptors and reuptake channels are not only present in the synaptic junctions themselves but are also scattered along the membranes of many nerve cells outside of synapses. Researchers believe that this mechanism extends the duration of dopamine’s influence on brain activity compared to the precise and localized effects of conventional synaptic transmission.

Dopamine’s effect on nerve cells depends on the type of receptors present in the cell. A neurotransmitter released into a synapse |  sciencepics, Shutterstock

Parkinson’s Disease: When Dopamine Runs Out

For many years, the close connection between dopamine and the development of Parkinson’s Disease has been well-known. Parkinson’s is a neurodegenerative disease that typically develops in older age, starting from the late 50s and onward. Its symptoms include tremors, slowness and stiffness in movement, speech difficulties, and more.

Dopamine’s presence in the brain was discovered as early as 1910. However, it was initially assumed to be merely an intermediate in the production of other active substances, without a direct functional role of its own. It wasn’t until the late 1950s that dopamine's true function was discovered. Researchers from Runwell Hospital in London demonstrated that severe dopamine deficiency in the brains of mice led to the loss of voluntary movement (Akinesia). Additionally, dopamine levels in specific brain regions of Parkinson’s patients were found to be drastically reduced. These early findings led to the first attempts to develop treatments for the disease.  In 1967, researcher George Cotzias successfully developed the drug L-DOPA, which provides the brain with some of the missing dopamine, thereby alleviating the symptoms of the condition. The drug remains widely used to this day.

The damage begins in dopamine-secreting cells located in the kernels of black matter - the substantia nigra - of the midbrain. These nerve cells project to the striatum, a brain region involved in motor control. In rats, for example, a single nerve cell in this pathway extends a total length of half a meter and can form hundreds of thousands of connections with cells in the striatum. In the human brain, these cells are believed to be even longer, with the number of connections they form reaching up to a million. Researchers believe that the immense workload exerted on these cells increases their vulnerability, with mass cell death of such cells leading to  Parkinson’s disease. Since treatments for the disease focus on increasing dopamine levels in the brain, they often come with substantial side effects, due to dopamine’s involvement in multiple neural signaling pathways in the brain.

In addition to Parkinson’s, dopamine system imbalances are also linked to schizophrenia. The main symptoms of schizophrenia include delusions, disorganized thinking, emotional blunting, and memory problems. The precise mechanisms connecting dopamine to this severe psychiatric disorder remains unclear, but in practice all current medications for schizophrenia compete with dopamine for binding to D2 receptors. Additionally, substances that increase dopamine activity, such as L-DOPA and certain drugs, exacerbate schizophrenia symptoms. At high doses, they can even induce schizophrenia-like symptoms in healthy individuals. Postmortem analyses have shown that the brains of schizophrenic patients contain an excess of dopamine and related compounds.

The area associated with the pleasurable sensation linked to reward attainment. Nucleus accumbens in the brain | MattL_Images, Shutterstock

Learning and Addiction

A distinct cluster of dopamine-producing cells is located in an area called the ventral tegmental area (VTA). These cells project to regions in the limbic system in the brain, which is responsible for emotional responses and emotional processing, as well as to areas of the cerebral cortex involved in advanced data processing and thought.

The first pathway is associated with learning, particularly associative learning that links positive reinforcement to a neutral stimulus in the environment or in the organism’s behavior. Contrary to earlier assumptions, dopamine is not released automatically in response to positive reinforcement, but rather only when the reward is unexpected. Furthermore, dopamine is released when a stimulus signaling an upcoming reward appears, and its levels decrease when the anticipated reward fails to materialize.

These findings led researchers to refer to this mechanism as “reward prediction error” - a concept borrowed from the field of computer science. This mechanism helps predict when a desired reward is likely to occur, allowing the organism to adjust its behavior accordingly. For example, an animal will work harder if it learns the behavior leads to a reward and will stop exerting effort if it realizes the behavior will not yield the desired reward. 

In the nucleus accumbens, the central endpoint of this pathway—called the mesolimbic pathway—dopamine activity is particularly sensitive to reinforcement and learning. This region is closely associated with the pleasure experienced when obtaining a reward. The second pathway, known as the mesocortical pathway, leads to other destinations, primarily the prefrontal cortex, which is associated with memory, attention, decision-making and maintaining motivation. These functions are influenced by learning and help the organism make beneficial decisions that are likely to yield positive rewards.

The learning system described here is a very effective system that enables fast and flexible learning, but it also has a dark side. Many psychoactive substances cause overstimulation of the dopamine system. This overstimulation induces intense feelings of pleasure, which accompany the release of dopamine and encourage the user to repeat the behavior in an attempt to recreate the pleasant sensation. That is how drug addiction is formed. 

Repeated use of drugs that activate the dopamine system can result in the development of tolerance, meaning increasingly higher doses are required to achieve the same pleasurable effect. Additionally, compensatory mechanisms lower dopamine levels in the brain in response to excessive release, creating dependency on the drug even for maintaining normal daily functioning. Researchers are also exploring whether the dopamine system plays a role in other types of addiction, such as gambling, shopping or social media addiction, but this will require further research.  

As with many processes in the body, dopamine release in the brain must occur in precise amounts and at the right timing. Dopamine is a neurotransmitter that plays a central role in various daily activities, such as movement and learning, and its release can elicit positive feelings of anticipation and excitement. It is no surprise that disruptions in dopamine activity can lead to far-reaching consequences, and even irreversible brain damage from drug exposure or severe diseases such as Parkinson’s and schizophrenia.