Pharmacology · ANS Introduction

Neurotransmitter Synthesis, Release, and Inactivation

Cholinergic and adrenergic transmission — drug targets at each step

Acetylcholine is synthesized from choline and acetyl-CoA by choline acetyltransferase, packaged into vesicles by the vesicular ACh transporter, released by calcium-triggered SNARE-mediated exocytosis, then rapidly hydrolyzed by acetylcholinesterase — each step is a distinct drug target, with botulinum toxin blocking release and organophosphates irreversibly inhibiting hydrolysis.
The catecholamine biosynthetic pathway runs from tyrosine → L-DOPA (rate-limiting step: tyrosine hydroxylase, blocked by metyrosine) → dopamine → norepinephrine (via dopamine β-hydroxylase in vesicles) → epinephrine (via PNMT in the adrenal medulla only, requiring glucocorticoid induction).
Carbidopa blocks peripheral DOPA decarboxylase without entering the CNS, preventing peripheral conversion of levodopa to dopamine — this is why the levodopa/carbidopa combination reduces peripheral dopaminergic side effects while preserving central therapeutic effect in Parkinson disease.
Norepinephrine termination at the synapse is dominated by reuptake via the NET transporter — cocaine blocks NET (and DAT), tricyclic antidepressants block NET, and atomoxetine selectively blocks NET for ADHD treatment; the intraneuronal catecholamines are metabolized by MAO-A (norepinephrine, serotonin) and MAO-B (dopamine).
VMAT-2 packages monoamines into storage vesicles — reserpine irreversibly blocks VMAT-2, depleting all monoamines and causing profound sympatholysis; tetrabenazine selectively blocks VMAT-2 in the CNS for Huntington disease chorea; COMT inhibitors (entacapone, tolcapone) extend levodopa half-life by blocking peripheral catecholamine degradation.

Mechanism	Primary Target	Drugs That Exploit This Step
Reuptake (NET)	Norepinephrine; also dopamine	Cocaine (NET + DAT block); tricyclic antidepressants; atomoxetine
MAO-A	Norepinephrine, serotonin	Phenelzine, tranylcypromine (irreversible); tyramine interaction risk
MAO-B	Dopamine, phenylethylamine	Selegiline, rasagiline — Parkinson disease adjuncts
COMT	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)

Suggested References

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