Neurotransmitters

Core Concepts

This article discusses neurotransmitters, including their classifications, their chemical structures, and what roles they play in the body. It takes a closer look at several well-known neurotransmitters, examines the specific mechanisms by which they function, and concludes with a discussion of the potential consequences when these systems malfunction.

Neurons and The Nervous System: A Glimpse at the Bigger Picture

The focus of this article is neurotransmitters, but it is helpful to first take a step back and look at the larger system in which they function to understand what role they play in the body. Therefore, let’s start with a brief discussion of neurons and the nervous system.

The nervous system is one of the eleven major body systems. It plays a key role in sensation, perception, thought and movement. The nervous system is made up of two main parts: the central nervous system (CNS), which consists of the brain and spinal cord, and the peripheral nervous system (PNS), which includes the nerves that extend from the brain and spinal cord to the rest of the body.

Neurons, also called nerve cells, are the basic functional unit of the nervous system. Neurons consist of three major parts:

• Cell Body (Soma): Contains the nucleus which produces energy for the cell.
• Dendrites: Branches extending off of the cell body that play a role in receiving signals from other cells.
• Axon: A long, slender nerve fiber extending off of the cell body which carries the nerve signal.
  • The region off of the cell body where the axon originates is referred to as the axon hillock. 
  • The axon is sheathed in a fatty substance called myelin, which aids in nerve signal conduction. Gaps in the myelin sheath are referred to as Nodes of Ranvier.
  • The axon ends in finger-like projections called axon terminals. Axon terminals contain small, sac-like structures (vesicles) where the neurotransmitters are synthesized and stored until released by an action potential (discussed later).

The space between adjacent neurons is known as the synaptic cleft. When discussing neuronal communication, the neuron sending a signal is referred to as the presynaptic neuron and the neuron receiving the signal is referred to as the postsynaptic neuron. Neurons communicate via chemical or electrical signals.

Neurotransmitters are the substances involved in chemical communication between adjacent neurons and permit the nervous system to perform a wide range of bodily functions and physiological processes.

Neurotransmitter Classification and Composition

Over 50 different types of neurotransmitters have been identified and scientists estimate there are many more that remain undiscovered. Those that have been identified are classified based on their structure or function.

Structural Classification:

Neurotransmitters are generally composed of small amine molecules, amino acids, or neuropeptides. As is often stated in biology, structure determines function—and neurotransmitters are no exception. They can be smaller, fast-acting molecules that produce localized effects, or larger, slow-acting molecules that produce longer-lasting effects.

• Amine Molecule Neurotransmitters
  • Structure: These neurotransmitters consist of a single amino group attached to an aromatic ring via a carbon-carbon chain.
  • Function: They play significant roles in cognitive processes such as emotional arousal, consciousness, attention, and memory formation.
  • Examples: Dopamine, Norepinephrine, Epinephrine, Histamine, Serotonin.

EX: Histamine

• Amino Acid Neurotransmitters
  • Structure: These neurotransmitters are composed of a single amino acid.
  • Function: They are crucial for arousal, sleep, consciousness, and sensory-to-motor processing.
  • Examples: Glutamate, Glycine, Gamma-Aminobutyric Acid (GABA).

EX: Glutamate

• Neuropeptides
  • Structure: They are made up of amino acid chains, typically consisting of 3 to 36 amino acids linked by peptide bonds.
  • Function: They are involved in diverse physiological processes, including satiation, learning, stress response, pain perception, and energy metabolism. They also serve as neuromodulators, modifying the strength and efficacy of synaptic signaling.
  • Examples: Endorphins.

EX: Endorphins

Functional Classification

Neurotransmitters are also classified as either excitatory or inhibitory based on their effect on the postsynaptic neuron.

• Excitatory: Excitatory neurotransmitters increase the likelihood that a neighboring cell will fire an action potential and the signal will continue. This is accomplished by producing actions that result in the inside of the cell becoming more positive, such as by opening sodium channels which allow positive charges to flood the inside of the cell. 
• Inhibitory: Inhibitory neurotransmitters decrease the likelihood that a neighboring cell will fire an action potential. This is accomplished by producing actions that result in the inside of the cell becoming more negative, such as by opening chloride channels which allow negatively charged chloride ions to enter the cell.

While neurotransmitters are classified as either inhibitory or excitatory based on their primary function, many are capable of producing either inhibitory or excitatory effects depending on their sites of action and which receptors they are communicating with. Furthermore, neurotransmitters can be classified as modulatory when they adjust the effects of other neurotransmitters to fine-tune communication between neurons.

A Closer Look at Some Common Neurotransmitters

While many neurotransmitters have been discovered, there are a few that have been well studied and found to perform major roles in the body. Some examples are the following:

• Acetylcholine: This neurotransmitter is secreted by neurons in many different areas of the nervous system. It is released at the neuromuscular junction where it stimulates muscle fibers to contract. It regulates certain functions of the parasympathetic nervous system – such as heart rate, digestion, and salivation – and also plays a role in the sleep-wake cycle, learning, memory, and attention. In most cases, acetylcholine produces excitatory effects; however, it can have an inhibitory effect at some peripheral nerve endings – such as when released by the vagus nerve to act on the heart and thereby decreasing muscle contraction.  

• Norepinephrine: Norepinephrine is secreted by neurons whose cell bodies are located in the brainstem and hypothalamus and send nerve fibers to widespread areas of the brain. It helps control overall activity and mood levels – such as increasing levels of wakefulness, alertness, and arousal. Norepinephrine also helps maintain blood pressure and is known for its major role in the body’s “fight or flight” response. Norepinephrine most commonly activates excitatory receptors and is structurally classified as an amine molecule neurotransmitter.

• Dopamine: Dopamine is a key player in the brain’s reward system. It is involved in the mesolimbic pathway and its release helps reinforce behaviors. It plays a role in mood, learning, attention, and memory formation. Dopamine is also involved in the nigrostriatal pathway which is involved in motor control. Dopamine can act as either an inhibitory or excitatory neurotransmitter, but its effects are usually inhibition. It is structurally classified as an amine molecule neurotransmitter.

• Glycine: This neurotransmitter is primarily inhibitory and is secreted in the brainstem and spinal cord. It is involved in motor coordination, visual and auditory sensory processing, and pain signaling. Glycine is an amino acid, and therefore this one is structurally classified as an amino acid neurotransmitter.

• Gamma-Aminobutyric Acid: GABA is the primary inhibitory neurotransmitter in the adult CNS. It is secreted by neurons in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. It plays a role in mood and sleep, and has a calming effect on the brain that produces a state of relaxation. GABA is an amino acid, and this one is therefore classified as an amino acid neurotransmitter. GABA is an amino acid, and this is structurally classified as an amino acid neurotransmitter.

• Glutamate: Glutamate is the most common excitatory neurotransmitter. It functions in many sensory pathways entering the central nervous system and is seen in many areas of the cerebral cortex. It plays a role in energy, mood, learning, pain signaling, and neuronal plasticity. Glutamate is an amino acid, and therefore this one is structurally classified as an amino acid neurotransmitter.

• Serotonin: Serotonin is primarily an inhibitory neurotransmitter that influences a range of functions including mood, appetite, digestion, sleep, and sexual behavior. It is crucial for maintaining emotional balance and general well-being. This neurotransmitter has a single amino group attached to an aromatic compound by a carbon-carbon chain and is therefore structurally classified as an amine molecule neurotransmitter.

How Do Neurons and Neurotransmitters Work?

Neurotransmitters rely on a highly precise mechanism of transmission to accomplish their tasks. Neurotransmission occurs via the generation of an action potential. The action potential originates when a signal is received by the dendrites of the soma. The soma then integrates these signals and, if the signal is strong enough, an action potential is initiated at the axon hillock. The signal is then carried down the axon in a unilateral direction towards the axon terminals, a phenomenon known as the principle of one-way conduction. 

The generation of an action potential involves several steps:

1. Resting Potential: A neuron that is not firing a chemical signal exists in a resting state with a membrane potential of about -70 millivolts (mV). In this state, the axon is negatively charged in relation to its environment. This state is maintained by sodium-potassium pumps, which actively transport ions to preserve the resting potential.
2. Depolarization: A stimulus, such as a neurotransmitter or electrical impulse, causes the membrane to become more permeable to sodium ions. More sodium ions enter the cell, causing the membrane potential to become less negative/closer to zero.
3. Rising Phase: The cell becomes less negative until it reaches threshold potential (typically around -50 to -55 mV). Neurons follow the all or none law, meaning that once threshold is met the neuron will fire an action potential. At this point, voltage-gated sodium channels open and sodium ions rush into the cell. 
4. Peak Action: The membrane potential reaches its maximum positive value, typically around 30 mV.
5. Repolarization: Sodium channels close and potassium channels open. Potassium ions rush out of the cell and down its electrochemical gradient, making the inside of the cell more negative to return to a resting state. A cell may briefly undershoot and become more negative than it is at resting state as ions rush out of the cell, an event which is referred to as hyperpolarization.
6. Refractory Period: For a brief period of time, the cell will not respond to any additional stimuli.

When an action potential reaches the axon terminals, it triggers the opening of calcium channels and the influx of calcium ions into the terminal. This produces a series of events that lead to the synaptic vesicles fusing with the cell membrane of the presynaptic neuron and releasing neurotransmitters into the synaptic cleft. The neurotransmitter will then diffuse across the gap and bind to receptors on the postsynaptic neuron where they produce either an inhibitory or excitatory action. After neurotransmitters complete their function, they can either diffuse away from the synaptic cleft, get reabsorbed (reuptake) and reused by the cell, or get broken down by enzymes (degradation). Clearing neurotransmitters away from the synaptic cleft is important for maintaining healthy communication and ensuring the postsynaptic neuron does not receive continuous stimulation.

What Could Go Wrong?

Disruptions in neurotransmitter function can lead to an array of issues. Examples of errors that can occur include:

• Overproduction or underproduction of neurotransmitters
• Malfunctioning receptors on the postsynaptic neuron 
• Dysfunction of enzymes that serve to regulate neurotransmitters levels
• Premature neurotransmitter reuptake, resulting in reduced time for signal transmission

When these problems occur, they can lead to an array of physical and mental symptoms. This includes difficulty sleeping, trouble learning and concentrating, muscle aches, tremors, and seizures. The specific symptoms and conditions that result depend on which neurotransmitters are affected. Such disruptions are linked to medical conditions including Alzheimer’s disease, Parkinson’s disease, depression, anxiety, schizophrenia, epilepsy, and myasthenia gravis.