Neurotransmitters: The Chemistry of the Brain

Your brain contains around 86 billion nerve cells, each connected to thousands of others. Signals travel along each nerve cell electrically, but at the tiny gaps between cells, called synapses, the message becomes chemical. Neurotransmitters are the molecules that carry it. Every thought, movement and feeling depends on them, and almost every drug that affects the mind works by changing how they’re released, detected or removed.

How a synapse works

1. An electrical signal (an action potential) reaches the end of a nerve cell.
2. Calcium ions flow in, triggering tiny vesicles full of neurotransmitter to fuse with the membrane and release their contents into the synaptic cleft, a gap about 20–40 nanometres wide.
3. The neurotransmitter diffuses across the gap in a fraction of a millisecond and binds to receptors on the next cell.
4. Receptors are either ion channels (which open and let ions flow, giving a fast response) or linked to G proteins (which trigger slower chemical cascades).
5. The signal is switched off by reuptake (transporters pump the neurotransmitter back into the nerve cell), enzymatic breakdown, or diffusion away.

A neurotransmitter can be excitatory (making the next cell more likely to fire) or inhibitory (less likely), depending on its receptors.

Here are the main neurotransmitters, grouped by chemical type.

Amino acids

1. Glutamate

• Chemistry: the anion of glutamic acid, one of the 20 standard amino acids.
• Role: the brain’s main excitatory neurotransmitter, used at most synapses. Essential for learning and memory.
• Note: too much glutamate activity can kill nerve cells (excitotoxicity), which contributes to damage after strokes. Glutamate is also the source of umami taste (see the chemistry of taste).

2. GABA (γ-aminobutyric acid)

• Chemistry: made from glutamate by removing a carboxyl group; its amino group is on the γ carbon, four carbons from the carboxyl group.
• Role: the brain’s main inhibitory neurotransmitter, calming nerve activity.
• Drugs: benzodiazepines (such as diazepam), barbiturates and alcohol all enhance GABA’s effects at GABA-A receptors, producing sedation and reducing anxiety.

3. Glycine

• Chemistry: the simplest amino acid.
• Role: the main inhibitory neurotransmitter in the spinal cord and brainstem.
• Note: the poison strychnine blocks glycine receptors, causing uncontrolled muscle spasms.

Monoamines

Small molecules made from amino acids, each with a single amine group.

4. Dopamine

• Made from: tyrosine, via L-DOPA.
• Role: movement control, motivation and reward learning.
• Note: loss of dopamine-producing cells causes Parkinson’s disease. See dopamine.

5. Noradrenaline (norepinephrine)

• Made from: dopamine.
• Role: alertness, attention and the stress response in the brain; also a neurotransmitter in the nerves that control the heart and blood vessels. Closely related to the hormone adrenaline.

6. Serotonin (5-hydroxytryptamine)

• Made from: tryptophan.
• Role: mood, sleep, appetite and gut function; most of the body’s serotonin is actually in the gut.
• Drugs: SSRIs, a common class of antidepressants, block its reuptake. See serotonin.

7. Histamine

• Made from: histidine.
• Role: wakefulness in the brain; in the body, it’s released in allergic reactions and stimulates stomach acid.
• Drugs: older antihistamines cross into the brain and block histamine receptors there, which is why they cause drowsiness.

Acetylcholine

8. Acetylcholine (ACh)

• Chemistry: an ester of acetic acid and choline, with a positively charged nitrogen (a quaternary ammonium ion).
• Role: the neurotransmitter at nerve–muscle junctions, making skeletal muscles contract; also important in memory and attention in the brain.
• Switching off: the enzyme acetylcholinesterase hydrolyses acetylcholine into acetate and choline extremely quickly, thousands of molecules per second.
• Drugs and poisons: nerve agents and some insecticides block acetylcholinesterase, so acetylcholine builds up with fatal effects (see enzyme inhibition). Nicotine activates one type of acetylcholine receptor. Curare, a plant-based arrow poison, blocks them, causing paralysis. Drugs that mildly inhibit acetylcholinesterase are used to treat Alzheimer’s disease symptoms.

Neuropeptides

9. Endorphins and enkephalins

• Chemistry: short peptides (5 to 31 amino acids).
• Role: natural painkillers acting on the same receptors as morphine. See endorphins.

10. Substance P, oxytocin and others

• Substance P (11 amino acids) carries pain signals in the spinal cord.
• Oxytocin (9 amino acids) acts both as a hormone and as a brain signal in social bonding (see the chemistry of attraction).

Neuropeptides are made by ribosomes, stored in larger vesicles, and generally act more slowly and for longer than small-molecule neurotransmitters.

Gases and other unusual messengers

11. Nitric oxide (NO)

• Chemistry: a small, reactive gas molecule with an unpaired electron (a radical).
• Role: made on demand from the amino acid arginine; it diffuses freely through membranes rather than being stored in vesicles. It relaxes blood vessels and plays roles in memory. Its discovery as a biological signal was recognised with the 1998 Nobel Prize in Physiology or Medicine.

12. Adenosine

• Chemistry: a nucleoside (adenine + ribose), related to ATP.
• Role: builds up during waking hours and promotes sleepiness. Caffeine blocks adenosine receptors, which is why coffee keeps you awake (see the chemistry of sleep).

13. Endocannabinoids

• Chemistry: lipid molecules such as anandamide, made from fatty acids in cell membranes.
• Role: unusually, they travel backwards across synapses, from the receiving cell to the sending cell, to dampen transmission. The active ingredient in cannabis, THC, acts on the same receptors.

Getting into the brain: the blood–brain barrier

The brain is protected by the blood–brain barrier: the cells lining its blood vessels are tightly joined and let through mainly small, fat-soluble molecules or those with dedicated transporters. That’s why:

• dopamine itself can’t be given to treat Parkinson’s disease (it doesn’t cross), but its precursor L-DOPA can, via an amino acid transporter;
• many drugs are designed to be fat-soluble enough to reach the brain, while others are designed not to, to avoid side effects.

How neurotransmitters were discovered

The idea that nerves communicate chemically was once controversial. In 1921, the German pharmacologist Otto Loewi performed a famous experiment, reportedly inspired by a dream. He stimulated the vagus nerve of a frog heart, which slowed its beat, then transferred the fluid bathing that heart to a second heart. The second heart slowed too, even though its own nerve hadn’t been stimulated. Some chemical, which Loewi called “Vagusstoff”, had been released. It was later identified as acetylcholine, and Loewi shared the 1936 Nobel Prize with Henry Dale. Since then, more than a hundred substances have been identified as neurotransmitters or neuromodulators.

Key takeaways

• Neurotransmitters carry signals across synapses, binding receptors on the next cell, and are removed by reuptake or breakdown.
• Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in the brain.
• Monoamines (dopamine, noradrenaline, serotonin, histamine) are made from amino acids and shape mood, attention and movement.
• Acetylcholine controls muscles and is broken down by acetylcholinesterase; neuropeptides, nitric oxide, adenosine and endocannabinoids add further layers of signalling.
• Most psychoactive drugs and many poisons act by mimicking, blocking or prolonging neurotransmitters. For the hormone side of chemical signalling, see hormones as chemical messengers.