Neurotransmitter Chemistry of the Autonomic Nervous System ~ Drugs & Therapeutics

Introduction:

An important traditional classification of autonomic nerves is based on the primary transmitter molecules—acetylcholine or norepinephrine—released from their terminal boutons and varicosities. A large number of peripheral ANS fibers synthesize and release acetylcholine; they are cholinergic fibers; that is, they work by releasing acetylcholine. These include all preganglionic efferent autonomic fibers and the somatic (nonautonomic) motor fibers to skeletal muscle as well. Thus, almost all efferent fibers leaving the CNS are cholinergic. In addition, most parasympathetic postganglionic and a few sympathetic postganglionic fibers are cholinergic. A significant number of parasympathetic postganglionic neurons utilize nitric oxide or peptides for transmission.

Most postganglionic sympathetic fibers release norepinephrine (also known as noradrenaline); they are noradrenergic (often called simply "adrenergic") fibers; that is, they work by releasing norepinephrine. As noted, a few sympathetic fibers release acetylcholine. Dopamine is a very important transmitter in the CNS, and there is evidence that it may be released by some peripheral sympathetic fibers. Adrenal medullary cells, which are embryologically analogous to postganglionic sympathetic neurons, release a mixture of epinephrine and norepinephrine. Finally, most autonomic nerves also release several cotransmitter substances, in addition to the primary transmitter

[Five key features of neurotransmitter function provide potential targets for pharmacologic therapy:

synthesis, storage, release, and termination of action of the transmitter, and receptor effects.]

Some of the Transmitter Substances Found in Autonomic Nervous System (ANS), Enteric Nervous System (ENS), and Nonadrenergic, Noncholinergic Neurons.¹

Substance	Probable Roles
Acetylcholine (ACh)	The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings. A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neuron-to-neuron ("ganglionic") transmitter in the ENS.
Adenosine triphosphate (ATP)	Acts as a transmitter or cotransmitter at many ANS-effector synapses.
Calcitoningene-related peptide (CGRP)	Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac stimulant.
Cholecystokinin (CCK)	May act as a cotransmitter in some excitatory neuromuscular ENS neurons.
Dopamine	A modulatory transmitter in some ganglia and the ENS. Probably a postganglionic sympathetic transmitter in renal blood vessels.
Enkephalin and related opioid peptides	Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate secretion.
Galanin	Present in secretomotor neurons; may play a role in appetite-satiety mechanisms.
GABA ( -aminobutyric acid)	May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter in the ENS.
Gastrin-releasing peptide (GRP)	Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin.
Neuropeptide Y (NPY)	Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and electrolytes by the gut. Causes long-lasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic neurons.
Nitric oxide (NO)	A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be especially important at sphincters. Synthesized on demand by nitric oxide synthase (NOS), not stored.
Norepinephrine (NE)	The primary transmitter at most sympathetic postganglionic nerve endings.
Serotonin (5-HT)	An important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS.
Substance P (related tachykinins)	Substance P is an important sensory neuron transmitter in the ENS and elsewhere. Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably via release of nitric oxide).
Vasoactive intestinal peptide (VIP)	Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant.