DUAL INNERVATION

• Each target organ has contact with two types of neurons that have different, generally opposing, actions, and distinct transmitter chemistry.

Sympathetic Division of the ANS

• One set of neurons innervating the target organs contains norepinephrine as the dominant transmitter type.

—because the catecholamines are related to each other biosynthetically, the sympathetic system also has some dopamine, and in some places norepinephrine

Parasympathetic Division of the ANS

• The other set of fibers innervating the target organs contains acetylcholine as the dominant transmitter type.

—like the sympathetic system, the parasympathetic system uses a number of peptide cotransmitters
—vasoactive intestinal peptide (VIP) is a probable cotransmitter in some parasympathetic neurons

ANATOMY

• The sympathetic and parasympathetic systems can be distinguished anatomically.

—the sympathetic ganglia lie adjacent to the spinal column in the paravertebral chain
—the parasympathetic ganglia lie in locations that are remote from the CNS

Preganglionic Fibers

• Preganglionic fibers emerge from the CNS to convey motor commands to the nerve cells in the ganglia.

—in the sympathetic system the preganglionic fibers are short, since they arise in the spinal cord and connect to the paravertebral chain adjacent to the cord
—the parasympathetic preganglionic fibers are long, since they must reach the target organs where the parasympathetic ganglia are located

Postganglionic Fibers

• The fibers that emerge from autonomic ganglia are called postganglionic fibers.

—sympathetic postganglionics are long since they must extend from the paravertebral chain to the target organ
—parasymapthetic postganglionics are short as the ganglia are typically located near the target organ
—the preganglionics for the sympathetic system all originate from the middle of the spinal cord
—the preganglionics for the parasympathetic system all originate from the top and bottom of the spinal cord

RECEPTORS

• There are two autonommic synapses to consider, the one connecting the preganglionic cell to the postganglionic cell, and the one connecting the postganglionic cell to the target organ.

Preganglionic Synapses

• Both the synpathetic and parasympathetic systems use acetylcholine as the transmitter connecting the preganglionics to the ganglia.

—the receptor subtype is the nicotinic cholinergic, the same one used by the somatic neuromuscular junction

Postganglionic Synapses

• The postganglionic fibers of the sympathetic division contain primarily norepinephrine, while those of the parasympathetic system use acetylcholine.

—norepinephrine receptors can be divided into alpha-adrenergic and beta-adrenergic
—the actions of the two systems are generally antagonistic to each other; if the sympathetic receptor is excitatory, the tissue will express an inhibitory parasympathetic receptor
—most of the time there is a balance between symapthetic and parasympathetic activity

NONSYNAPTIC RELEASE

• In some cases the autonomic postganglionic contact is a true synapse.

—often, however, the contact is a looser network of terminals called a plexus
—the site of release at such a network is called a varicosity
—each varicosity contains electron-rich vesicles that contain the catecholamine transmitter, along with other substances such as dopamine-beta-hydroxylase
—varicosities also contain dense-cored vesicles, the function of which is currently debated
—fibers that form a nerve plexus tend to be small and unmyelinated, thus slow

Second and Third Messengers

• The action of transmitters is sometimes slow because there are sometimes several steps between the ligand binding to the receptor and the biological effect.

—the receptors for autonomic transmitters lack channels altogether
—the channel affected lies elsewhere in the membrane
—a complex chain of enzymatically catalyzed events takes place inside the cell
—the autonomic receptors are therefore enzymes, not channels
—one example of these events is acetylcholine binding to the muscarinic receptor
—the enzyme associated with the muscarinic receptor is called a G protein
—when acetylcholine binds to the receptor, the G protein activates a second enzyme, phospholipase C
—phospholipase C breaks up some phospholipid called phosphatidylinositol biphosphate (PIP2) into inositol triphosphate, and diacylglycerol (DAG)
—PIP2 and DAG are second messengers, having a wide range of actions on intracellular processes
—acetylcholine can be excitatory or inhibitory, depending on both the receptor and the specific G protein involved
—intracellular signalling systems are related to many important and varied brain processes, including vision, learning, and cell development

THE ADRENAL GLAND

• The adrenal glands sit directly on top of the kidneys, and make adrenaline (epinephrine) from norepinephrine.

—the enzyme phenylethanolamine N-methyltransferase (PNMT) makes epinephrine from norepinephrine
—the adrenal gland is like a large sympathetic ganglia, receiving cholinergic innervation and secreting its products directly into the bloodstream
—most of the targets of the adrenal gland receive sympathetic innervation, and most of their receptors have overlapping affinity for epinephrine and norepinephrine

The Fight-or-Flight Response

• The state of arousal in response to danger is called the fight-or-flight response.

—the body is prepared for physical emergencies
—changes of the fight-or-flight response include heart rate increases, lung airway dilation, glucose release, and pupillary constriction
—many specialists in behavioral medicine believe that the fight-or-flight response may be currently maladaptive, and may be related to disorders like hypertension

Transmitters, Hormones, and Everything in Between

• The body possesses a continuum of chemical signaling mechanisms, including neurotransmitters, neurohormones, hormones, and pheromones.

—the complexity of membrane proteins reflects the degree of specificity demanded of them
—voltage-gated ion channels share sequence homology, and are composed of a single strand of protein that crosses the membrane many times
—ligand-gated channels tend to be made up of polymers of separate proteins, each polymer crossing the membrane many times
—receptors expressed by autonomic targets are made up of a different family of homologous proteins
—these receptors typically are single strands that span the membrane seven times, but are not attached to channels directly
—this last family of receptors are called G protein-coupled receptors
—the ion channel is another protein, called the G protein-linked channel
—examples of this kind of receptor are the muscarinic, dopamine, serotonin, and numerous peptides

Glucose Mobilization

• Glucose mobilization is an example of a hormonally interacting with a G protein-coupled receptor.

—the adrenal hormone epinephrine has effects on hepatocytes (liver cells)
—each hepatocyte expresses beta-adrenergic receptors
—beta-adrenergic receptors interact with G proteins which activate an enzyme called adenylate cyclase
—adenylate cyclase catalyzes the production of cyclic adenosine monophosphate (cAMP) from ATP
—cAMP activates protein kinase which adds phosphate groups to its substrate, phosphorylase kinsase
—each phosphorylase kinase adds a phosphate to its substrate, glycogen phosphorylase
—glycogen phosphorylase acts on glycogen to produce free glucose
—chemical messengers are often used to perform tasks more complex than opening or closing a channel
—the cAMP/protein kinase system amplifies the "dim" message of the hormone

HOW "AUTONOMIC" IS IT?

• The body is constantly experiencing a tension or balance between sympathetic and parasympathetic tone.

—occasions of sympathetic dominance are associated with arousal
—most situations of sympathetic dominance have a volitional component (e.g., bungee jumping)
—autonomic functions can proceed without our awareness
—whether awareness can increase our control of autonomic function is an important and controversial question

THE SPECIAL CASE OF SEX

• Male reproductive function is a classic example of the two systems working in concert with each other.

—erections are produced by parasympathetic activity, while ejaculations are produced by sympathetic activity
—the genitalia are innervated by tiny sympathetic ganglia that lie in the innervated organ, not in the paravertebral chain

THE SENSORY COMPONENT

• Many autonomic nerves are not motor but sensory.

—sensation from the viscera is mostly pain information, called nociception

"Referred Pain"

• The autonomic sensory fibers join with fibers of the somatic system and then enter the spinal cord.

—thus fusion leads to confusion about visceral and somatic function in the CNS
—referred pain is sometimes perceived as arising from the body surface instead of from within
—an example is angina pectoris, perceived pain in the left arm and shoulder that is caused by insufficient oxygen to the heart
—migraine headaches may be due to referred pain from blood vessels in the head

THE ENTERIC NERVOUS SYSTEM AND OTHER SIMPLE SYSTEMS

• The gut has intrinsic networks of sensory and motor fibers that function independently of the CNS and autonomic innervation.

—the sympathetic ganglia that innervate the gut are remote from the paravertebral chain and are part of the enteric nervous system

TRANSMITTERS COMMON TO THE ANS AND CNS

• The major autonomic transmitters, norepinephrine and acetylcholine, also turn up in the brain with their major receptor types.

Modes of Action

• Both autonomic transmitters have been implicated in a number of behaviors.

—slices of rat hippocampus let us mimic the "simple systems" approach
—in this preparation, acetylcholine appears to act on muscarinic receptors, and norepinephrine appears to act on beta-adrenergic receptors, as in the periphery
—however, the two transmitters effects on hippocampal neurons are both inhibitory, as opposed to their opposite effects in the periphery
—each appears to shut down a calcium-activated potassium channel that allows the cells to fire more action potentials

Autoreceptors

• The presynaptic structure also expresses receptors for the transmitter released, called autoreceptors.

—the autoreceptors are generally different receptors than the ones expressed postsynaptically
—an example is an excitatory postsynaptic beta-adrenergic receptor and an inhibitory presynaptic alpha-adrenergic receptor

Turnover and Breakdown

• Turnover and breakdown of neurotransmitters are the sources of yet more differences between transmitters.

—norepinephrine, for example, is sometimes taken up intact by the presynaptic cell and packaged for rerelease without being degraded
—many drugs that act on the autonomic system affect turnover or breakdown of the transmitters
—cocaine, for example, blocks the re-uptake mechanism for dopamine and norepinephrine
—viagra inhibits the breakdown of the third messenger in the penis and leads to longer erections

Peptide Action in Gut and Brain

• Peptides in the autonomic nervous system also generally have been found in the brain.

—examples include VIP, insulin, and glucagon

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