Neurotransmitters: Messenger Molecules in the Brain

Information processing in the brain depends on networks of nerve cells communicating with each other via synapses. But how exactly do the cells communicate with each other? For a long time, researchers assumed that an electrical current flows between the cells – an obvious hypothesis, since information is primarily transmitted within a single nerve cell as an electrical action potential.

In fact, there are those so-called electrical synapses that connect neurons, known as gap junctions. However, they are in the minority in our nervous system. Most synapses communicate with each other chemically – a method that was impressively demonstrated 1921 by the scientist Otto Loewi (see info box). Since then, many of his successors have studied the chemical transmission of electrical excitation at synapses and discovered that they offer far more diverse possibilities than a simple electrical contact point.

The messenger substances that transmit information at chemical synapses are called neurotransmitters. Through painstaking puzzle work, scientists have been able to identify dozens of these substances to date. They can be divided into different classes (see info box). The best known are probably serotonin and dopamine, both of which are also considered “happiness hormones” – more on that later. However, other neurotransmitters are crucial in the majority of chemical synapses: in most excitatory synapses, glutamate is the carrier of information, while in inhibitory synapses it is GABA (gamma-aminobutyric acid) or glycine.

Neurotransmitters usually migrate from the presynapse of the sending neuron across a synaptic cleft to a postsynaptic membrane, which may be located on the axon, dendrites, or cell body of another receiving nerve cell. They are produced on the output side, i.e., in the presynapse, and stored in small vesicles. When an action potential arrives, the vesicles empty into the synaptic cleft. At the postsynaptic membrane, the transmitter molecules fit to specific receptor proteins like a key in a lock. There they can have an excitatory or inhibitory effect, depending on the transmitter itself and, in many cases, on the specific receptor type (see info box). In any case, this creates an input that the postsynaptic neuron can process together with signals coming in from elsewhere.

After signal transmission, it's time to clean up: in order for the synapse to become functional again, the transmitter molecules must disappear from the gap. At least for those substances that are responsible for rapid communication, the presynaptic membrane helps: transport proteins ensure that the transmitter is reabsorbed into the neuron. There it is either recycled or broken down.

Each transmitter, therefore, needs a specially tailored mechanism to ensure that synthesis, release, effect, and reuptake function smoothly. Many drugs, medications, and even poisons interfere with this complex biochemical cycle by activating or blocking transmitter receptors or inhibiting reuptake.

Since nerve cells specialize in one or a few transmitters, messenger substances can often be assigned to specific neuron networks. Particularly well-known and significant examples of such neurotransmitter systems are the cholinergic system around the transmitter acetylcholine, the serotonergic system with the messenger substance serotonin, and, analogously, the dopaminergic system with the neurotransmitter dopamine. These three will be discussed in more detail below.

A special feature of these three networks is that they have relatively small areas of origin, meaning that they are only produced by specific, narrowly defined groups of neurons. However, their influence extends to over 100,000 synapses and more per participating neuron in many different areas of the brain. In addition, acetylcholine, serotonin, and dopamine have a slower, longer-lasting effect than glutamate, for example, because they are not only released in a single synapse, but diffused in a larger area (so-called volume transmission). They therefore play a special role in regulating comprehensive states such as sleep, wakefulness, or mood. A textbook therefore compares these networks, known as “diffuse modulatory systems”, to the treble and bass controls on a radio: although they cannot change the vocals and melody, they can drastically influence their effect.

Acetylcholine was probably the first neurotransmitter to be discovered because it plays a crucial role in the autonomic nervous system and at the interface between motor nerves and skeletal muscles. But cholinergic neurons are also found in the brain. The most important of these can be summarized as two diffuse modulation systems.

One system innervates the hippocampus, neocortex, and olfactory bulb from the base of the cerebrum (between and below the basal ganglia). These cells are among the first to die in Alzheimer's disease. The extent to which there is a connection to the disease beyond this is unclear. However, among the approved Alzheimer's drugs, which are intended to at least delay the loss of mental abilities, there are active ingredients that slow down the breakdown of acetylcholine in the brain. The second system consists of cells in the pons and tegmentum of the midbrain. It acts primarily on the thalamus, but also strongly on the cerebrum.

Cholinergic neurons are involved in controlling attention and brain excitability during sleep and wakefulness rhythms. Animal experiments have shown that acetylcholine promotes the transmission of sensory stimuli from the thalamus to the relevant regions of the cortex. It also appears to play a crucial role in plasticity and learning.

Serotonin is also widespread outside the central nervous system. It was first isolated in the mucous membrane of the gastrointestinal tract. The name comes from its effect on blood pressure: as a component of serum, it regulates the tension (tone) of blood vessels. As a neurotransmitter in the brain, serotonin is only detectable in neurons whose cell bodies are located in the so-called raphe nuclei in the brain stem. From there, their axons innervate virtually all regions of the brain and influence pain perception, sleep-wake rhythms, and mood, among other things. The raphe nuclei are particularly active in states of heightened alertness and least active during sleep. Conversely, studies have shown that excess serotonin in the brain can cause restlessness and hallucinations. Serotonin deficiency can lead to depressive moods, anxiety, and aggression.

Serotonin is found in many foods but cannot enter the brain via the bloodstream. Instead, it is produced locally from the amino acid tryptophan. However, the amount of serotonin in the brain can be influenced by tryptophan levels – and these, in turn, can be influenced by diet. A diet rich in carbohydrates leads to high tryptophan availability, while conversely, studies have shown that carbohydrate withdrawal causes sleep disorders and depression, which has been attributed to the resulting serotonin deficiency. Many antidepressants and anti-anxiety medications specifically increase the amount of serotonin available in the brain, for example by slowing down presynaptic reuptake. These active ingredients are known as selective serotonin reuptake inhibitors (SSRIs).

Nevertheless, mood cannot simply be improved by increasing serotonin levels. This is also demonstrated by treatment experience with SSRIs: although the active ingredients reach the brain quickly, they only take effect after several weeks of use, and only in cases of severe depression do they achieve clearly demonstrable success.

Dopamine, like norepinephrine and epinephrine – other neurotransmitters that are particularly important in the peripheral autonomic nervous system (think of the famous “adrenaline rush”) – is produced from the amino acid tyrosine. Before animal experiments rather accidentally revealed its independent significance for the central nervous system, dopamine was long considered only a chemical precursor of norepinephrine.
Dopamine-containing cells are found in many places in the central nervous system, but two dopaminergic neuron groups are of particular importance. One is located in the substantia nigra in the midbrain and sends its axons to the striatum. This pathway is important for controlling voluntary movements: if the dopaminergic cells in the substantia nigra degenerate, this triggers fatal motor disorders – Parkinson's disease.

The second dopaminergic system also originates in the midbrain, in the ventral tegmental area. From there, the axons extend to certain parts of the cerebrum and the limbic system. This pathway is therefore also known as the mesocorticolimbic system and is believed to play an important role in motivation: it is considered a reward system that reinforces behaviors that are beneficial to survival in both animals and humans. Increasing the amount of dopamine available through appropriate active substances has a stimulating effect – but often also leads to addiction. A well-known example is cocaine: it inhibits the reuptake of dopamine, promoting alertness, increased self-esteem, and euphoria; at the same time, this stimulation of the reward system is addictive.

Other symptoms and mental illnesses are also associated with disorders of the dopamine system. Schizophrenia, for example, is linked to an overactive dopamine system, while a lack of dopamine in the frontal cortex is thought to contribute to attention deficit hyperactivity disorder (ADHD).

First published: February 2, 2018
Last updated on August 5, 2025