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Acetylcholine is synthesized by choline acetyltransferase and released at the neuromuscular junction and throughout the CNS. ACh acts on nicotinic receptors (ionotropic, fast, excitatory) and muscarinic receptors (metabotropic, slow, modulatory). Cholinergic neurons in the basal forebrain promote arousal and attention; loss in Alzheimer's disease contributes to cognitive decline.
Study neuromuscular junction as prototypical cholinergic synapse. Trace ACh pathways in brain using anatomical atlases.
ACh is always excitatory. ACh at nicotinic receptors is excitatory; at muscarinic it can be inhibitory.
You already understand how synaptic transmission works at a general level and have studied the neuromuscular junction as a model synapse. Acetylcholine (ACh) is the neurotransmitter at that junction, and it was in fact the first neurotransmitter ever identified — Otto Loewi demonstrated its existence in 1921 by showing that stimulating the vagus nerve released a chemical substance that slowed a second heart. ACh is synthesized in the presynaptic terminal by the enzyme choline acetyltransferase (ChAT), which transfers an acetyl group from acetyl-CoA to choline. After release, ACh is rapidly broken down in the synaptic cleft by acetylcholinesterase (AChE), one of the fastest enzymes known, terminating the signal within milliseconds.
What makes the cholinergic system uniquely instructive is that a single neurotransmitter produces dramatically different effects depending on which receptor it binds. Nicotinic receptors (named because nicotine activates them) are ligand-gated ion channels — the ionotropic receptors you already know. When ACh binds, the channel opens within microseconds, allowing Na⁺ and K⁺ to flow, producing a fast excitatory postsynaptic potential. This is the mechanism at the neuromuscular junction that triggers muscle contraction. Muscarinic receptors (named after the mushroom toxin muscarine) are metabotropic — they are G-protein coupled receptors that activate intracellular signaling cascades. Muscarinic signaling is slower (hundreds of milliseconds to seconds) and can be either excitatory or inhibitory depending on the receptor subtype and the G-protein it couples to. In the heart, muscarinic M2 receptors open potassium channels that slow heart rate — this is what Loewi's experiment detected.
In the brain, cholinergic neurons are concentrated in a few small nuclei but project widely, much like a sprinkler system that modulates large territories rather than delivering point-to-point messages. The basal forebrain cholinergic system (including the nucleus basalis of Meynert) sends projections throughout the cortex and hippocampus, where ACh promotes attention, arousal, and memory encoding. When you focus on a task and irrelevant stimuli fade from awareness, cortical ACh release is part of what makes that possible. This is why the degeneration of these neurons in Alzheimer's disease produces such devastating cognitive effects — the cortex loses its attentional and memory-encoding modulator. Drugs like donepezil work by inhibiting acetylcholinesterase, prolonging the action of whatever ACh remains.
The peripheral cholinergic system is equally critical. ACh is the neurotransmitter at all preganglionic autonomic neurons (both sympathetic and parasympathetic), at parasympathetic postganglionic neurons, and at the neuromuscular junction. This broad distribution explains why cholinergic drugs and toxins have such widespread effects: nerve agents like sarin inhibit AChE, causing uncontrolled ACh accumulation at every cholinergic synapse simultaneously — muscles lock in contraction, glands hypersecrete, and the heart slows dangerously. Understanding the anatomy of the cholinergic system is therefore essential for both neuroscience and pharmacology.