Neuroscience · Unit 2: Synapses and plasticity
Transmitter Systems and Drugs
A handful of chemicals carry most of the brain's synaptic traffic, and each one comes as a system: where it is made, which receptors read it, and how it is switched off. This lesson compares acetylcholine, glutamate, GABA, glycine, the amines and the peptides on those three points, then sorts drugs by what they do to that system. Afterwards you can classify a drug's action, calculate how much of a target a drug occupies, and say what a drug's mechanism does and does not prove about a disease.
Watch first A Drug Acts On One Step · 3:12
Paroxetine binds the human serotonin transporter so tightly that 0.08 nanomolar fills half of the transporters in a dish. Ten times that fills about 90%. Neither number tells you why some depressed people improve on it.
To see why, you need two things this lesson builds. The first is a map of the brain’s transmitter systems: who releases each chemical, what reads it, and what turns it off. The second is a way of classifying drugs by which of those steps they change, and of keeping a drug’s mechanism separate from a story about a disease. The release step itself, vesicles fusing and quanta, is in synaptic transmission.
The idea: a transmitter is a system with a source, readers and an off switch
A transmitter system has three parts. The source is the set of neurons that make and release the chemical. Several systems come from a nucleus, a cluster of neuron cell bodies inside the brain, whose axons spread widely. The readers are the receptors. An ionotropic receptor is itself an ion channel and acts in about a millisecond; a metabotropic receptor is a G-protein-coupled receptor (GPCR) that acts in tens of milliseconds to seconds through messengers inside the cell. The receptor classes are surveyed in the receptor field guide and GPCRs and G proteins. The off switch ends the signal: an enzyme that breaks the transmitter down, a transporter that carries it back into a cell, or for peptides, peptidases.
Think of a radio station: a transmitter tower, the sets that tune to it, and the moment the broadcast stops. A drug can boost the tower, jam or fake the signal, or keep the broadcast running.
One rule before the list. A transmitter is not excitatory or inhibitory by nature. The receptor and the ion gradient decide. GABA opens chloride channels, and it usually inhibits because chloride’s equilibrium potential in most mature neurons sits near or below rest (the sign switch during development is in CNS synapses). How transmitters are synthesized from amino acids belongs to amino acids in the biochemistry course; here you need only where they are made, released and cleared.
The fast amino acids: glutamate, GABA and glycine
Glutamate is the brain’s main excitatory transmitter. In the textbook account nearly all excitatory neurons in the central nervous system release it, so its source is everywhere rather than one nucleus. It acts at three ionotropic receptors (AMPA, kainate and NMDA) and at metabotropic glutamate receptors. High-affinity transporters in glia and presynaptic terminals clear it from the cleft; there is no glutamate-destroying enzyme in the cleft.
GABA is the main fast inhibitory transmitter of the brain. It is made by local interneurons, neurons whose axons stay within a region, and also by projection neurons: cerebellar Purkinje cells and the spiny projection neurons of the striatum are classic examples. GABA-A receptors are ligand-gated chloride channels; GABA-B receptors are GPCRs formed from two subunits, GB1 and GB2. Neurons and glia both take GABA back up through high-affinity transporters.
Glycine carries much of the inhibition in the spinal cord, through strychnine-sensitive chloride channels, and transporters remove it. It has a second job. In cultured mouse brain neurons, Johnson and Ascher found that glycine potentiated NMDA receptor responses by a mechanism separate from the inhibitory glycine receptor. The NMDA receptor needs a co-agonist at this site, which is glycine or, in some rat preparations, D-serine; its role as a coincidence detector is in ion channels as receptors.
Acetylcholine and the amines
These systems come from small groups of neurons whose axons reach large territories, which is why a drug acting on one can change arousal, mood or movement at once.
| Transmitter | Major source | Receptors | Off switch |
|---|---|---|---|
| Acetylcholine | Basal forebrain; laterodorsal and pedunculopontine tegmental nuclei | Nicotinic channels; muscarinic GPCRs | Hydrolysis by acetylcholinesterase |
| Dopamine | Substantia nigra and ventral tegmental area (midbrain) | D1-like (D1, D5) and D2-like (D2, D3, D4) GPCRs | Uptake by DAT |
| Noradrenaline | Locus coeruleus (pons) | α1, α2 and β GPCRs | Uptake by NET |
| Serotonin | Dorsal and median raphe nuclei (brainstem) | GPCRs, plus the 5-HT3 channel | Uptake by SERT |
Two cautions about the table. The sources are the major ones, not the only ones: these are review syntheses drawn largely from rodent anatomy. And not every amine receptor is a GPCR. In 1989 Derkach, Surprenant and North recorded single-channel currents opened by serotonin in outside-out patches from guinea-pig enteric neurons, showing that the 5-HT3 receptor is a ligand-gated channel.
Acetylcholine is the one in the table ended by an enzyme. Acetylcholinesterase hydrolyses it at many cholinergic synapses, most famously the neuromuscular junction. The amines are ended by transporters, membrane carriers that use the sodium gradient to move the transmitter back into the terminal. SERT’s reuptake depends on sodium and chloride.
Dopamine deserves one more caution, since you will meet it again in motivation and reward and the basal ganglia. Popular accounts reduce it to a signal for pleasure. Recordings and manipulations in animals tie its signals instead to reward prediction, movement and motivation, among other roles, and those lessons give the evidence.
Peptides and co-transmission
Neuropeptides are short chains of amino acids packaged in large dense-core vesicles. Neuropeptide Y, for example, is made by neurons spread throughout the brain. Most neuropeptides act at GPCRs, and peptidases cut them into inactive fragments, so reuptake is not their main off switch as it is for the amines.
A neuron can release more than one transmitter. In adult mouse slices, dopamine neurons of the substantia nigra inhibit striatal projection neurons by releasing GABA, and Melani and Tritsch (2022) found that this GABA depends on uptake through the transporter Gat1. So “a dopamine neuron” names a cell’s main transmitter, not its only one, and a drug aimed at one transmitter of a neuron may leave its partner untouched.
How drugs act, and what that does not prove
Drugs fall into a few classes by what they do to a system.
- An agonist activates a receptor: baclofen at GABA-B receptors.
- A competitive antagonist binds the agonist’s own site and prevents activation: bicuculline at GABA-A receptors.
- A positive allosteric modulator binds a different site and strengthens the agonist’s effect: benzodiazepines such as diazepam bind at an interface of GABA-A subunits separate from the GABA sites.
- A reuptake blocker occupies a transporter: paroxetine and S-citalopram sit in the central site of SERT, where serotonin binds.
- An enzyme inhibitor slows breakdown: donepezil reduced cortical acetylcholinesterase activity, measured by PET, in patients with probable Alzheimer disease. That is a mechanism, not a measure of clinical benefit.
The quantitative side of binding is in binding and dose-response. Here is the version you need.
Worked problem: how much transporter does a drug occupy? Coleman, Green and Gouaux (2016) reported paroxetine binding to wild-type human SERT in HEK293 cell membranes and reported a dissociation constant, KD, of 0.08 nM. The dissociation constant is the free drug concentration at which half the binding sites are filled. Assume one class of site, equilibrium, and so little binding that free drug equals added drug.
f = L / (KD + L)
Here f is the fraction of transporters occupied and L the free drug concentration.
Step 1. At L = 0.08 nM: f = 0.08 / (0.08 + 0.08) = 0.50. Half the transporters are occupied, which is what KD means.
Step 2. What L gives 90%? Rearranging, L = f × KD / (1 − f) = 0.90 × 0.08 nM / 0.10 = 0.72 nM. Check: 0.72 / (0.08 + 0.72) = 0.72 / 0.80 = 0.90.
Step 3. For 99%: L = 0.99 × 0.08 nM / 0.01 = 7.92 nM. That is 11 times the concentration needed for 90%, all to fill the last 9% of sites. Occupancy curves flatten at the top.
Step 4. Contrast two drugs at a receptor, using made-up round numbers. Suppose GABA gives half its maximal current at a GABA-A receptor at 10 µM (its EC50). A competitive antagonist with a dissociation constant KB = 1 µM, present at [B] = 3 µM, shifts the curve right by the dose ratio:
dose ratio = 1 + [B] / KB = 1 + 3/1 = 4
The apparent EC50 becomes 40 µM, and enough GABA still reaches the same maximum. A benzodiazepine does the opposite kind of thing: it shifts the GABA curve to the left and opens no channels by itself.
Keep these numbers in their place. Occupancy of SERT in membranes is not efficacy, not a change in synaptic serotonin, and not a dose for a person.
- Occupancy at your L
- 50.0%
- L needed for the target
- 0.72 nM
- times the L for 90% (above 90% only)
- 1.00
In this sketch: one class of site, equilibrium, free drug equal to added drug; paroxetine at wild-type human SERT in HEK293 membranes, reported KD = 0.08 nM (Coleman, Green and Gouaux, 2016).
Occupancy f = L / (KD + L) climbs steeply at first and flattens at the top, so filling the last sites takes far more drug than filling the first.
That limit matters most for depression. SSRIs block SERT; that is established. The step from there to “depression is caused by low serotonin” is a separate claim. A 2022 umbrella review by Moncrieff and colleagues found no consistent support for depression being caused by lowered serotonin concentration or activity. A separate question is whether the drugs help: a 2018 network meta-analysis by Cipriani and colleagues found all 21 antidepressants it included more effective than placebo for acute major depression in adults, with certainty of evidence from moderate to very low. Both findings can be true at once. Aspirin relieves a headache, and headaches are not caused by a lack of aspirin.
Design problem
Delgado and colleagues (1990) gave 21 patients whose depression had remitted on antidepressants a tryptophan-free amino-acid challenge, which lowers the precursor of serotonin, and a control challenge, double-blind and in crossover. Fourteen of the 21 relapsed after tryptophan depletion; the control challenge had no significant effect. Does this show that low serotonin causes depression? If not, what would you need to test that claim?
One way to do it
It does not. The patients were selected because they had responded to antidepressants, most of which act on serotonin or noradrenaline systems. The result suggests that remission in some treated patients depends on serotonin being available. A treatment can depend on a transmitter that was never low to begin with.
To test whether low serotonin causes depression, you would study people who are not on these drugs. Deplete tryptophan, with a balanced control drink that contains tryptophan, in people who have never been depressed and in untreated people with depression, double-blind and in crossover. If lowering serotonin caused depression, never-depressed people should develop symptoms and untreated patients should worsen. Measure mood with blinded raters, check that blood tryptophan actually fell, and report how many participants changed, not only group means.
Then weigh the result against the wider evidence: the 2022 umbrella review found no consistent support for a low-serotonin cause. Keep the efficacy question, which Cipriani and colleagues addressed, separate: whether a drug helps is a different question from what caused the illness.
How we measure it
Outside-out patch clamp
A pipette sealed onto a neuron is pulled away so that a small patch of membrane closes over its tip with the outer face toward the bath. You apply a transmitter to the bath and record single-channel currents. A response that survives without the cytoplasm points to a receptor that gates its own channel.
Radioligand binding
Membranes carrying a target, such as SERT expressed in HEK293 cells, are incubated with a radioactive drug at a range of concentrations, and bound drug is separated and counted. A fit to a binding model gives the dissociation constant, KD. It measures affinity, not what the drug does once bound.
X-ray crystallography and cryo-electron microscopy
Purified receptors or transporters are imaged with a drug bound, and the map shows which residues line the drug's pocket. Each structure is one state, so it must be paired with functional recordings before you say whether binding opens, blocks or modulates.
Blinded crossover depletion challenge
Each participant receives a challenge that lowers a transmitter's precursor on one occasion and a matched control on another, with neither participant nor rater knowing which. Each person serves as their own control, and the result applies to the population that was enrolled.
Finish line
Test yourself
8 questions
Practice and MCAT-style, with explained answers.
Next · Lesson 7
Integration, Inhibition and Neuromodulation
An inhibitory input can move the membrane potential by zero millivolts and still stop the cell from firing. How?
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