Autonomic Nervous System Series  ·  Module 2

Neurotransmitter Synthesis, Release, and Inactivation

Cholinergic and adrenergic transmission — drug targets at each step

Acetylcholine Lifecycle

Step 1

Synthesis

Choline + Acetyl-CoA → ACh via choline acetyltransferase

Hemicholinium-3 blocks choline uptake (experimental)

Step 2

Storage

ACh packaged into vesicles by vesicular ACh transporter

Vesamicol blocks vesicular transporter (experimental)

Step 3

Release

Ca²⁺-triggered exocytosis via SNARE complex

Botulinum toxin cleaves SNARE proteins → blocks release

Step 4

Inactivation

Acetylcholinesterase hydrolyzes ACh → choline + acetate

Organophosphates (irreversible) and carbamates (reversible) inhibit acetylcholinesterase

Catecholamine Biosynthetic Pathway

Tyrosine

Dietary amino acid

↓Tyrosine HydroxylaseRate-limiting step • Blocked by metyrosine

L-DOPA

Levodopa (prodrug)

↓DOPA DecarboxylaseBlocked peripherally by carbidopa

Dopamine

CNS neurotransmitter

↓Dopamine β-HydroxylaseIn synaptic vesicles; requires ascorbate

Norepinephrine

Sympathetic post-ganglionic

↓PNMT (adrenal medulla only)Requires glucocorticoids for induction

Epinephrine

Adrenal medulla (~80%)

MechanismPrimary TargetDrugs That Exploit This Step
Reuptake (NET) Norepinephrine; also dopamine Cocaine (NET + DAT block); tricyclic antidepressants; atomoxetine
Monoamine oxidase-A Norepinephrine, serotonin Phenelzine, tranylcypromine (irreversible); tyramine interaction risk
Monoamine oxidase-B Dopamine, phenylethylamine Selegiline, rasagiline — Parkinson disease adjuncts
Catechol-O-methyltransferase All catecholamines; peripheral levodopa Entacapone, tolcapone — extend levodopa effect in Parkinson disease
VMAT-2 block (storage) All monoamines (depletion) Reserpine (antihypertensive/depression risk); tetrabenazine (Huntington disease)