Full mechanism, in text

How nerve cells pass messages

1 · Resting · NT loaded in vesicles

At rest, the presynaptic terminal pumps NT into vesicles with transporters and keeps calcium channels ready, while the postsynaptic membrane holds ion-channel and G-protein coupled receptors.The synapse is the ~ 20-40 nm chemical gap between two neurons in the brain — all learning, memory, emotion, and motor control happens one event at a time in this narrow slit.

Presynaptic terminal equipped with:

· Hundreds of synaptic vesicles, each ~ 40 nm diameter, holding 2000-10000 NT molecules
· VMAT / VGAT / VGLUT transporters actively pump cytosolic NT into vesicles (~ 1000× against concentration gradient)
· Cav2 calcium channels (P/Q/N type) wait at the active zone
· Mitochondrial clusters supply nearby

Postsynaptic membrane equipped with:

· Ionotropic receptors (ion channel type): NMDA / AMPA (glutamate) · -A · nicotinic ACh · glycine — millisecond-scale switches
· Metabotropic receptors (G-protein coupled): mGluR · GABA-B · dopamine D1-5 · receptors 14 subtypes · adrenergic — second-to-minute modulation

Nutrition anchors:

· GABA (gamma-aminobutyric acid) synthesis: GAD enzyme + B6 (PLP) cofactor
· Dopamine: Tyr → DOPA by the TH enzyme (needs iron and BH4), DOPA → dopamine by AADC (needs B6)
· 5-HT: Trp → by the TPH enzyme (needs iron and BH4), then AADC (B6) makes 5-HT
· NE: dopamine → NE, DBH enzyme + copper + vitamin C
· ACh: choline + acetyl-CoA, ChAT enzyme

Key asymmetry: neurotransmitter synthesis is a closed-loop negative feedback — supplementing the precursor ≠ making more NT, the premise for understanding where many psychiatric drugs act.

2 · AP → Ca²⁺ → SNARE → release

When the action potential arrives, calcium channels open and the calcium sensor drives the SNARE complex to fuse vesicles with the membrane, releasing NT into the synaptic cleft.Action potential (AP) arrives at the presynaptic terminal, triggering a strictly ordered millisecond cascade:

A · Depolarisation → Cav2 calcium channel opens
· At rest cytoplasm Ca²⁺ ~ 100 nM; after channel opens local concentration jumps 100-1000× instantly (to µM range)
· Spatial precision: only Ca²⁺ within 20-50 nm of the active zone is enough to trigger fusion, anything farther isn't enough

B · Synaptotagmin calcium sensor
· Synaptotagmin on the vesicle binds Ca²⁺ → conformational change → drives the SNARE complex to execute fusion
· Each vesicle has ~ 15 synaptotagmin, forming a trigger switch array

C · SNARE complex fusion (Südhof 2013 Nobel)
· v-SNARE (vesicle-side synaptobrevin) + t-SNARE (membrane-side syntaxin-1 + SNAP-25) 3 helices wind into a 4-strand bundle
· The winding-tight process forcibly pulls together vesicle membrane with presynaptic membrane, releasing ~ 35 kJ/mol of energy to overcome phospholipid repulsion
· Fusion pore opens → NT bursts out of the vesicle in one shot into the synaptic cleft (≤ 1 ms)

D · Quantal release
· One action potential releases 5-50 vesicles (vesicle = quantum unit)
· Probabilistic event: single-vesicle release probability ~ 0.1-0.5, not definitely released
· Synaptic strength is regulated by two variables: release probability + receptor count

Drugs / toxins intervening at this step:

· Botulinum toxin (Botox) → cleaves SNAP-25 / syntaxin → completely blocks release → muscle paralysis / cosmetic wrinkle removal
· Tetanus toxin → cleaves SNARE of inhibitory neurons → inhibition gone → spasm
· Benzodiazepines (appears in step 3, not this step)

3 · NT binds · excite vs inhibit

NT diffuses across the gap and binds postsynaptic receptors, and the receptor decides whether the signal excites or inhibits, and whether it is fast or slow.NT crosses the 20-40 nm gap (diffusion time < 0.1 ms) and binds postsynaptic receptors. Receptors decide the signal's nature + speed:

Ionotropic (ion-channel, ms-scale):

· Glutamate → AMPA / NMDA / kainate → Na⁺ in → depolarisation → EPSP excitation
· NMDA is unique: requires glutamate + glycine/D-serine + membrane depolarisation to dislodge the Mg²⁺ plug simultaneously → coincidence detector, the molecular basis of LTP / learning + memory (the magnesium scene covers this plug)
· → GABA-A → Cl⁻ in → hyperpolarisation → IPSP inhibition
· Benzodiazepines (diazepam, alprazolam) bind an allosteric site on GABA-A, increasing Cl⁻ channel opening frequency → sedation / anxiolysis / anticonvulsant
· Ethanol also acts on GABA-A → one reason people drink to relieve anxiety, and a source of withdrawal risk
· Glycine → glycine receptor → Cl⁻ in → inhibition (mainly in spinal cord / brainstem)
· Strychnine blocks → generalised convulsions (see the glycine story)

Metabotropic (G-protein coupled, s-min scale):

· Dopamine D1-D5 — D1/D5 excitatory, D2-D4 inhibitory. Antipsychotics (haloperidol / risperidone) mainly block D2.
· 14 subtypes — 5-HT2A is the psychedelic (LSD / psilocybin) receptor; 5-HT3 is the ondansetron antiemetic site.
· G-protein downstream: Gs↑ cAMP / Gq↑ IP3-Ca²⁺ / Gi↓ cAMP — second messengers regulate ion channels + transcription, don't open gates directly

Key teaching point: Excitation vs inhibition isn't decided by the NT, it's decided by the receptor — the same NT on different receptors can go either way. Serotonin makes you happy is an oversimplification; the reality is 14 subtypes doing completely different things in different brain regions.

4 · Termination · reuptake and enzymatic clearance

NT must be cleared fast, either pulled back into the presynaptic terminal by transporters or broken down by enzymes, and many psychiatric drugs act on these two routes.NT must be rapidly cleared, or signals blur. Two main termination mechanisms. Many psychiatric drugs plug in here ( / / ), but not all — benzodiazepines and antipsychotics act at the receptors instead:

A · Reuptake

The presynaptic terminal surface carries NT-specific transporters that pull NT from the cleft back into the cytosol (most enter vesicles for reuse):

· SERT (serotonin transporter) — reuptake
· SSRIs (fluoxetine / sertraline / escitalopram) block SERT → 5-HT stays longer in the cleft → deeper receptor activation → antidepressant (onset ~ 4-6 weeks, because the real changes are downstream receptors + BDNF + neuroplasticity)
· DAT (dopamine transporter) — dopamine reuptake
· Cocaine / amphetamines block DAT → synaptic dopamine surges several-fold (amphetamines usually more than cocaine) → intense reward / addiction
· Methylphenidate (Ritalin) / amphetamine (Adderall) — ADHD meds also work here, but dose + PK differ
· NET (norepinephrine transporter) — NE reuptake
· SNRIs (venlafaxine / duloxetine) block SERT + NET simultaneously — antidepressant + chronic pain
· Bupropion mainly NE + DA dual block — antidepressant + smoking cessation
· Tricyclic antidepressants (TCAs) — old drugs, multi-target (SERT + NET + anti-ACh + α-adrenergic + antihistamine) → effective but many side effects + high overdose cardiac toxicity, replaced by SSRIs/SNRIs as first-line

B · Enzymatic degradation

· AChE (acetylcholinesterase) — hydrolyses ACh into acetate + choline in the synaptic cleft
· AD drugs donepezil / galantamine block AChE → ACh accumulates → partial improvement of early-to-mid AD cognition (mechanism correct, but limited clinical effect — AD isn't just ACh deficiency)
· Organophosphate pesticides / sarin nerve gas irreversibly inhibit AChE → systemic cholinergic crisis (tearing / drooling / incontinence / convulsions / death)
· MAO (monoamine oxidase) A / B — degrades 5-HT / DA / NE / tyramine in cytosol
· MAOIs (phenelzine / selegiline) block MAO → old antidepressants, with certain foods (aged cheese = tyramine) → cheese reaction hypertensive crisis, restricting clinical use
· L-deprenyl (selegiline) selective MAO-B inhibition → early-Parkinson's drug
· COMT — mainly degrades extrasynaptic dopamine, Parkinson's drug entacapone inhibits COMT alongside L-DOPA

Key points:

· The synapse is the chemical bridge — many psychopharmacology sites fit on this diagram
· Any NT's final effect = release × receptor × termination — single-point interventions (precursor supplementation) give weak returns; multi-target drugs (SSRIs directly hit termination) give strong returns
· / tryptophan supplements lift mood: with endogenous SERT + MAO simultaneously clearing, cleft concentration rises briefly then drops; co-administration with SSRIs carries serotonin syndrome risk
· Choline supplements boost memory: AChE clears excess ACh immediately, cleft concentration can't be controlled to rise; real anti-AD benefit comes from AChE inhibitors, not supplementing the precursor

See precursor → synthesis → release → binding → termination as five steps on one diagram, and the sites where many psychiatric drugs act all fall into place.

Full mechanism, in text

1 · Resting · NT loaded in vesicles

2 · AP → Ca²⁺ → SNARE → release

3 · NT binds · excite vs inhibit

4 · Termination · reuptake and enzymatic clearance

Synapse · the chemical bridge

Full mechanism, in text

1 · Resting · NT loaded in vesicles

2 · AP → Ca²⁺ → SNARE → release

3 · NT binds · excite vs inhibit

4 · Termination · reuptake and enzymatic clearance

Synapse · the chemical bridge