Neurotransmitter

Classical neurotransmission usually follows a sequence: Synthesis, Storage, Release, Receptor binding, and Termination.

Synthesis

Neurotransmitters must first be made by the neuron. Small-molecule transmitters, such as dopamine, acetylcholine, glutamate, and GABA, are usually synthesised in or near the axon terminal by local enzymes. Neuropeptides are different: because they are short chains of amino acids, they are made in the cell body using the neuron's protein-making machinery, then processed and transported down the axon.

For many transmitters, one key enzyme controls how much of the transmitter the neuron can produce. Tyrosine hydroxylase is important for catecholamines such as dopamine and norepinephrine; choline acetyltransferase is important for acetylcholine; and glutamic acid decarboxylase, or GAD, converts glutamate into GABA.

Storage

Once made, most classical neurotransmitters are packed into vesicles: tiny membrane-bound sacs inside the presynaptic terminal. Specific vesicular transporters load different transmitters into these vesicles. VGLUT loads glutamate, VGAT loads GABA, and VMAT2 loads monoamines such as dopamine, norepinephrine, and serotonin.

This packaging matters because it keeps transmitter molecules ready for rapid release. It also allows neurotransmitter to be released in small, discrete packets, with each vesicle contributing one "quantum" of signal. Neuropeptides are packaged into larger dense-core vesicles in the cell body and then transported to nerve terminals.

Release

When an action potential reaches the axon terminal, the terminal membrane depolarises. This opens voltage-gated calcium channels, especially P/Q-type and N-type channels at many fast synapses. Calcium then flows into the terminal.

That calcium signal triggers synaptic vesicles to fuse with the presynaptic membrane through the SNARE fusion machinery. The vesicle opens into the synaptic cleft and releases its neurotransmitter. This process is called exocytosis. It is extremely fast and tightly controlled.

Release is not all-or-nothing at the level of the whole terminal. The neuron can change how likely vesicles are to release, how many vesicles are available, and how strongly the presynaptic terminal responds to incoming signals. These changes are one important basis of synaptic plasticity.

Receptor binding

After release, neurotransmitter diffuses across the synaptic cleft, a tiny gap usually about 20–40 nanometres wide. It then binds to receptors on the postsynaptic cell.

There are two major receptor types.

Ionotropic receptors are ligand-gated ion channels. When neurotransmitter binds, the receptor opens an ion channel directly. This produces very fast effects, usually within milliseconds. Examples include AMPA and NMDA glutamate receptors, GABA-A receptors, and nicotinic acetylcholine receptors.

Metabotropic receptors are usually G-protein-coupled receptors, or GPCRs. They do not open ion channels directly. Instead, they activate intracellular signalling pathways that can change ion channels, enzyme activity, gene expression, or the cell's overall responsiveness. Their effects are slower, often lasting seconds to minutes or longer. Examples include muscarinic acetylcholine receptors, dopamine receptors, metabotropic glutamate receptors, and most serotonin receptors except 5-HT₃.

The same neurotransmitter can have different effects depending on which receptor it binds to. Dopamine is a good example. D1-family receptors generally increase cAMP signalling, while D2-family receptors generally decrease it. But the final effect depends on the cell type, circuit, ion channels present, and receptor location. So dopamine is not simply "excitatory" or "inhibitory"; its effect depends on context.

Termination

The signal must then be stopped. Otherwise, the neurotransmitter would keep activating receptors and the message would lose precision.

Termination happens in several ways. Some neurotransmitters are taken back up into the presynaptic terminal or nearby glial cells by transporters. SERT clears serotonin, DAT clears dopamine, and EAATs help clear glutamate, especially through astrocytes.

Some transmitters are broken down by enzymes. Acetylcholinesterase breaks down acetylcholine in the synaptic cleft. Monoamine oxidase and catechol-O-methyltransferase help degrade monoamines such as dopamine and norepinephrine.

Some transmitter molecules simply diffuse away from the synapse.

This termination step is medically important. Many drugs act here: SSRIs block serotonin reuptake, cocaine blocks dopamine reuptake, acetylcholinesterase inhibitors prolong acetylcholine signalling, and several other drugs alter transmitter clearance or breakdown.

Neurotransmitters are conventionally grouped by chemical structure.

Small-molecule transmitters

Glutamate

Glutamate is the main excitatory neurotransmitter in the central nervous system. It is used throughout the brain and spinal cord to help neurons activate one another.

Glutamate acts through two major receptor families. Ionotropic glutamate receptors, including AMPA, NMDA, and kainate receptors, produce fast excitatory signals. Metabotropic glutamate receptors produce slower, modulatory effects.

The NMDA receptor is especially important because it is both voltage-dependent and permeable to calcium. This makes it central to synaptic plasticity, including long-term potentiation, a process involved in learning and memory. However, excessive glutamate signalling can be harmful. Too much activation can cause calcium overload and neuronal injury, a process called excitotoxicity, which is implicated in stroke, traumatic brain injury, and some neurodegenerative diseases.

GABA

GABA, or γ-aminobutyric acid, is the main inhibitory neurotransmitter in the central nervous system. Where glutamate usually increases the likelihood that a neuron will fire, GABA usually reduces it.

GABA acts through two main receptor types. GABA-A receptors are ionotropic chloride channels that produce fast inhibition. GABA-B receptors are metabotropic receptors that produce slower, longer-lasting inhibition, partly by opening potassium channels and reducing calcium entry.

GABA is made from glutamate by the enzyme glutamic acid decarboxylase, or GAD. This means the brain's main excitatory and inhibitory neurotransmitters are chemically very close: one enzymatic step separates glutamate from GABA.

Dopamine

Dopamine is a modulatory neurotransmitter involved in reward, motivation, movement, learning, and executive function. Rather than simply turning neurons "on" or "off," dopamine often changes how circuits respond to other signals.

Four major dopamine pathways are especially important.

• Mesolimbic pathway. Involved in reward, motivation, and addiction.
• Mesocortical pathway. Contributes to cognition and executive function.
• Nigrostriatal pathway. Supports motor control and is affected in Parkinson's disease.
• Tuberoinfundibular pathway. Regulates prolactin release, so dopamine disruption here can contribute to hyperprolactinaemia.

Dopamine is also central to reward prediction error. In simple terms, phasic dopamine activity can signal the difference between what was expected and what actually happened. This idea has strongly influenced modern models of reinforcement learning.

Acetylcholine

Acetylcholine was the first neurotransmitter identified as a chemical mediator of nerve signalling. Henry Dale characterised its pharmacological actions, while Otto Loewi's 1921 frog-heart experiment showed that nerves could communicate through a chemical signal. Loewi called this substance Vagusstoff, later confirmed to be acetylcholine.

Acetylcholine has several major roles. At the neuromuscular junction, it allows motor neurons to activate skeletal muscle through nicotinic acetylcholine receptors. In the central nervous system, it has broader modulatory functions, especially in attention, arousal, learning, and memory. It acts through both nicotinic and muscarinic receptor subtypes.

Cholinergic neurons in the basal forebrain, including the nucleus basalis of Meynert, project widely to the cerebral cortex. Degeneration of these neurons is an important feature of Alzheimer's disease.

Neuropeptides

Neuropeptides are a large and diverse group of signalling molecules made from short chains of amino acids. They include endorphins, enkephalins, substance P, neuropeptide Y, oxytocin, vasopressin, cholecystokinin, orexin/hypocretin, and many others.

Unlike many small-molecule neurotransmitters, neuropeptides are made as larger precursor proteins in the cell body. They are processed through the Golgi apparatus, packaged into dense-core vesicles, and transported down the axon.

Neuropeptides are often co-released with classical neurotransmitters. They usually act through G-protein-coupled receptors and tend to produce slower, more diffuse, and longer-lasting effects. Their signalling can extend beyond a single synapse through volume transmission, allowing them to modulate broader neural circuits rather than only one tightly defined postsynaptic target.

Other signalling molecules

Some signalling molecules do not fit the classical neurotransmitter model. Nitric oxide and endocannabinoids, such as anandamide and 2-AG, are not stored in synaptic vesicles and released in the usual presynaptic-to-postsynaptic direction. Instead, they are often made on demand when the cell needs them.

These molecules can also signal "backwards." Endocannabinoids, for example, are commonly produced by the postsynaptic cell and travel back to the presynaptic terminal, where they reduce further neurotransmitter release. This is called retrograde signalling. Acting mainly through CB1 receptors, endocannabinoids help fine-tune synaptic strength and are involved in both short-term and long-term forms of synaptic depression across the brain.

Nitric oxide is even more diffuse. As a gas, it can pass through cell membranes and affect nearby cells without being packaged into vesicles or released through ordinary exocytosis.

Dale's principle is often summarized as "one neuron, one transmitter," but that phrase is too simple. A more careful version is that a neuron tends to release the same transmitter, or same set of transmitters, from its terminals. Even this is best understood as a historical guideline rather than a strict biological law.

Modern neuroscience shows that many neurons release more than one signalling molecule. A neuron may release a primary small-molecule transmitter, such as glutamate, GABA, acetylcholine, or dopamine, together with one or more co-transmitters, often neuropeptides.

Co-transmission gives neurons more flexibility. The same neuron can produce different effects depending on how often it fires, which vesicles are released, and which receptors are present on the target cell. Small-molecule transmitters are usually released rapidly during ordinary signalling, while neuropeptides often require stronger or higher-frequency activity. This allows one neuron to send both fast, precise signals and slower modulatory signals.

Many psychoactive drugs — therapeutic and recreational — act on neurotransmitter systems, whether by targeting receptors, transporters, synthetic or degradative enzymes, or release machinery.

Depression and anxiety. Selective serotonin reuptake inhibitors (SSRIs) block SERT, increasing serotonin availability in the cleft. Serotonin–norepinephrine reuptake inhibitors (SNRIs) block both SERT and NET. The monoamine hypothesis of depression — that depression results from insufficient monoamine signalling — has been a productive clinical framework, though it is recognised as incomplete. Ketamine's rapid antidepressant effect, mediated via NMDA receptor antagonism and downstream effects on synaptic plasticity, has opened new models.

Schizophrenia. The dopamine hypothesis proposes that positive symptoms (hallucinations, delusions) arise from excessive dopaminergic activity in the mesolimbic pathway, while negative and cognitive symptoms reflect hypodopaminergia in the mesocortical pathway. Most antipsychotics used for schizophrenia block D2 receptors to some degree, though exceptions exist — pimavanserin, approved for Parkinson's disease psychosis, acts primarily as a 5-HT2A inverse agonist and largely avoids D2 antagonism. Glutamatergic models — based on the observation that NMDA receptor antagonists (PCP, ketamine) produce schizophrenia-like symptoms — have expanded the picture.

Parkinson's disease. Caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine depletion in the striatum and the characteristic motor triad of bradykinesia, rigidity, and resting tremor. Levodopa (L-DOPA), the metabolic precursor of dopamine, remains the gold-standard treatment.

Myasthenia gravis. An autoimmune disorder in which antibodies target nicotinic acetylcholine receptors at the neuromuscular junction, producing fatigable skeletal muscle weakness. Acetylcholinesterase inhibitors (e.g. pyridostigmine) are a mainstay of symptomatic treatment.

Epilepsy. Many anticonvulsants work by enhancing GABAergic inhibition (benzodiazepines potentiate GABA-A receptors; vigabatrin inhibits GABA transaminase) or by reducing glutamatergic excitation (perampanel blocks AMPA receptors). Others act on voltage-gated sodium or calcium channels rather than directly on neurotransmitter systems.

Addiction. Drugs of abuse converge on the mesolimbic dopamine system. Cocaine blocks DAT; amphetamines reverse DAT to cause dopamine efflux; opioids disinhibit VTA dopamine neurons via mu-opioid receptors on GABAergic interneurons; nicotine activates nicotinic receptors on VTA dopamine neurons directly. The resulting supraphysiological dopamine signal drives reinforcement learning that progressively shifts from goal-directed drug seeking to habitual compulsion.

Nerve agents and organophosphate poisoning. Organophosphates irreversibly inhibit acetylcholinesterase, causing uncontrolled accumulation of acetylcholine at both muscarinic and nicotinic synapses — producing a characteristic cholinergic crisis (salivation, lacrimation, urination, defecation, bronchospasm, bradycardia, muscle fasciculations, paralysis).