Neurotransmission in the central nervous system
How brain cells talk through chemical messengers, and how sedatives, antidepressants, antipsychotics and other CNS drugs change that conversation.
Almost every drug that acts on the brain works at the synapse: it changes how a transmitter is made, stored, released, detected or removed. Knowing the main transmitter systems (glutamate, GABA, the monoamines, acetylcholine and the neuropeptides) makes the effects and side effects of CNS drugs predictable.
The synapse, step by step
An action potential opens calcium channels in the nerve terminal; calcium triggers vesicles to fuse and release transmitter into the cleft. The transmitter binds receptors on the next cell and is then cleared: amino acids and monoamines by reuptake transporters, acetylcholine by acetylcholinesterase, neuropeptides by peptidases. Clearing keeps each signal brief.
- Synthesis: levodopa is the precursor that the brain turns into dopamine
- Storage: VMAT2 inhibitors (tetrabenazine) empty monoamine vesicles
- Reuptake: SSRIs block the serotonin transporter
- Breakdown: cholinesterase inhibitors (donepezil) and MAO inhibitors slow removal
Excitation and inhibition: glutamate and GABA
Glutamate acts on ionotropic AMPA, NMDA and kainate receptors and on metabotropic receptors. NMDA antagonists such as ketamine (anaesthesia) and memantine (dementia) dampen it. GABA-A receptors are chloride channels: benzodiazepines and z-drugs make GABA more effective at its own site, barbiturates also hold the channel open, which is why they are more dangerous in overdose. Many antiseizure medicines tip the balance toward inhibition or reduce glutamate release.
- Benzodiazepines need GABA to work; flumazenil reverses them at the same receptor
- Gabapentinoids bind a calcium-channel subunit and reduce transmitter release
- Mixing CNS depressants (alcohol, opioids, benzodiazepines) adds up, with risk of breathing depression
The monoamines and acetylcholine
Dopamine pathways handle movement (nigrostriatal), reward (mesolimbic) and prolactin control (tuberoinfundibular). Noradrenaline from the locus coeruleus sets arousal; serotonin from the raphe nuclei touches mood, sleep, appetite and nausea. Acetylcholine in the basal forebrain supports memory, which is why anticholinergic drugs can cause confusion in older adults. Antidepressants raise monoamine signalling; antipsychotics block dopamine D2 receptors (see serotonin and dopamine pharmacology).
Neuropeptides and other messengers
Peptides such as endorphins, enkephalins, substance P and orexin are often released together with a classic transmitter and act slowly on G protein-coupled receptors. Opioids mimic the endogenous opioid peptides; NK1 antagonists (aprepitant) block substance P in the vomiting centre; orexin antagonists promote sleep. Endocannabinoids, nitric oxide and ATP are further signals that drugs can target.
Thinking like a pharmacologist
For any CNS drug, ask three questions: which transmitter, which receptor, which pathway. The answer predicts both the wanted effect and the typical adverse effects. Combining two drugs that raise serotonin, for example, can cause serotonin syndrome, with agitation, tremor, fever and muscle rigidity.
Test yourself
Think of the answer, then tap the question to see it.
Why are benzodiazepines safer in overdose than barbiturates when taken alone?
Benzodiazepines only increase the effect of GABA that is already present at the GABA-A receptor, while barbiturates can also open the chloride channel directly, so their effect has no ceiling.
Which receptor do ketamine and memantine block?
The NMDA type of glutamate receptor.
How do metabotropic receptors differ from ionotropic receptors?
Ionotropic receptors are ion channels that open in milliseconds; metabotropic receptors act through G proteins and second messengers, so their effects are slower and last longer.
Why can an antipsychotic cause parkinsonism?
It blocks dopamine D2 receptors in all dopamine pathways, including the nigrostriatal pathway that controls movement.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Serotonin syndrome: MedlinePlus Medical Encyclopedia (MedlinePlus (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.