Introduction to the Autonomic Nervous System

1. Introduction to the Autonomic Nervous System PHAR 417: Fall 2005 Dr. Thomas Abraham Department of Pharmaceutical Sciences Campbell University School of Pharmacy

2. Autonomic Nervous System Overview Overview of the Peripheral Autonomic Nervous System • Autonomic Nervous System: • Involuntary • Not necessary for immediate maintenance of life • Function to maintain homeostasis

3. Autonomic Nervous System Overview • Anatomical distribution of the Autonomic Nervous System • Parasympathetic neurons originate in the midbrain, medulla oblongata and sacral spinal cord. • Sympathetic neurons originate from the thoracic and lumbar portions of the spinal cord.

4. The Parasympathetic Nervous System • The parasympathetic nervous system (PNS) is responsible for discreet changes in organ function e.g. increased salivation or lacrimation or urination or sexual arousal, etc. •  Associated with “Rest and digest” phenomenon • Preganglionic fibers emerge from brain stem or sacral portion of spinal cord and are generally long. The ganglia with the postganglionic nerves are thus usually found within the innervated tissue. • Cranial nerves III, VII, IX and X supply the muscles of the eyes, salivary glands, heart, lungs, and GI tract. • Sacral nerves supply the descending colon, rectum, urinary bladder and erectile tissue.

5. Parasympathetic Nervous System

6. The Parasympathetic Nervous System

7. The Parasympathetic Nervous System Control of Pupil Diameter by the Parasympathetic Nervous System Control of Accommodation by the Parasympathetic Nervous System Sphincter muscle supplied by PNS Radial muscle supplied by SNS • Cholinergic neurons innervate the circular or sphincter muscles of iris to cause miosis (pupilary constriction) • Cholinergic neurons cause contraction of smooth muscles of ciliary body to causes fattening of the lens and thus accommodation for near sight

8. The Parasympathetic Nervous System • The effect of ACh on postsynaptic tissue is terminated by rapid action of Acetylcholinesterase (AChE) that metabolizes ACh to acetate and choline:

9. The Parasympathetic Nervous System Neurotransmission in the ganglia is achieved by preganglionic fibers releasing acetylcholine (ACh) into the synaptic space, which activates Nicotinic, cholinergic (N)receptors on postganglionic nerve dendrites. • Nicotine from tobacco is able to bind and activate the ganglionic nicotinic receptor to enhance ganglionic transmission. • -CNS effects: • -Neuromuscular junction effects: • Depolarization of postganglionic cholinergic nerves results in the release of stored ACh within the innervated tissue, that activates Muscarinic, cholinergic (M) receptors to produce biological effects.

10. The Parasympathetic Nervous System • Liberated choline is taken into the nerve terminal (blocked by hemicholinium-3) where it is conjugated to acetate by Choline Acetyltransferase (ChAT) to produce ACh. • Synthesized ACh is transported into synaptic vesicles where is released upon subsequent depolarization of the nerve terminus. Uptake of ACh into vesicles is blocked by vesamicol. • ACh is able to activate a number of muscarinic receptors to initiate specific signal transduction pathways in certain cells types to produce biological response:

11. Parasympathetic Nervous System

12. The Sympathetic Nervous System • Fundamental role of the SNS is to allow the animal to respond to stressful situations i.e. fight or flight response. • The sympathetic chain ganglion (paravertebral chain ganglion) allows simultaneous activation of multiple organ systems. • Pre-synaptic sympathetic neurons originating in the T1-L5 portion of spinal cord innervate the chain ganglia.

13. The Sympathetic Nervous System Effector Organ Spinal cord • Preganglionic nerves synapsing in the chain ganglia: • 1.are generally short. • 2.      release acetylcholine as the primary neurotransmitter. • Post-ganglionic nerves: • 1.leave the chain ganglia to innervate specific effector organs. • 2.are generally longer than pre-ganglionic nerves. • release (-) norepinephrine as the primary neurotransmitter.

14. The Sympathetic Nervous System Synthesis and Release of Norepinephrine from Sympathetic nerve endings • The amino acid tyrosine is converted to dopamine which is taken into vesicles where it is converted to norepinephrine. NE is stored in the vesicle with ATP and neuropeptide Y. • Depolarization of the nerve terminal results in the fusion of the neurotransmitter vesicles with the synaptic membrane resulting in release of the contents into synaptic cleft.

15. The Sympathetic Nervous System • Released norepinephrine: • 1.Interacts with specific adrenergic receptors to produce tissue/organ response. • - postsynaptic response. • - presynaptic modulation of further neurotransmitter release.

16. The Sympathetic Nervous System 2.is taken back into the nerve terminal by Uptake 1 process. - blocked by cocaine, phenoxybenzamine - after uptake NE can be incorporated into vesicles or metabolized by MAO 3.is taken into post-synaptic tissue by Uptake 2 process. 4.metabolized by MAO or Catechol-O-methyltransferase to inactive intermediates and finally to homovanillic acid (HVA) methoxyhydroxy mandelic acid (VMA).

17. The Sympathetic Nervous System

18. The Sympathetic Nervous System

19. The Sympathetic Nervous System • Regulation of adrenergic neurotransmitter release • Pre-synaptic receptors on sympathetic nerve terminals influence • the release of norepinephrine: • 1.a2-adrenergic and muscarinic M1, 2 receptors decrease NE release. •   2.AT1-angiotensin and nicotinic N receptors increase NE release. a2 M2 NE Adrenergic Receptors on Effector Organ Nerve Terminal NE NE NE NN AT1

20. The Sympathetic Nervous System Adrenergic receptors and their effector systems

21. Integration of Autonomic Function Generally the parasympathetic system causes discrete changes in organ function and usually associated with “rest & digest”: -         increased salivary secretion -         increased GI motility -         increased urination, defecation -         increased bronchial constriction, secretions -         decreased heart rate -         pupillary constriction, decreased visual accommodation -         increased sexual arousal Parasympathetic activity does not usually cause generalized organ system activation unless: -acetylcholine metabolism is significantly inhibited (nerve gas, insecticides) -exposure to muscarinic agonists (muscarine from mushrooms)

22. Integration of Autonomic Function • Sympathetic nervous system is designed to provide more wide-spread activation of organ systems during severe stress; assured by interconnections between ganglia in the chain ganglia that allow almost simultaneous activation of multiple nerve bundles supplying different organs. • Sympathetic activation prepares the organism to flee from or fight a potential threat: • -         pupils dilate, lens flatten for far-vision • -         heart rate, force increased • -         vasoconstriction • -         blood shunted from viscera to skeletal muscle • -         increased respiration rate • -         glucose release by liver • -         kidney blood flow and water loss decreased • -         GI and bladder function decreased • -         Skin blood flow decreased, piloerection • Sympathetic and parasympathetic systems do not oppose each other: • parasympathetic tone is decreased to specific organs with increased sympathetic tone and vice versa.

23. Somatic Nervous System: motor end plate • Myelinated motor neurons originating in the spinal cord have cell bodies in the ventral horn • Motor neurons are controlled by higher motor centers in the brain. • ACh released at the nerve terminal activates nicotinic NM receptors on the motor end-plate of skeletal muscle cells.

24. Naturally occuring Toxins that affect Cholinergic Neurotransmission • Botulinum toxin from Clostridium botulinum degrades synaptobrevin, a membrane protein required for binding of the vesicle to the nerve terminal membrane. The toxin decreases ACh release from cholinergic and motor nerves. • VAMPs and SNAPs (like synaptobrevin) interact in the presence of Ca2+ to produce fusion of vesicles with terminal membrane • BoTox® used in the treatment of spastic disorders, ocular disorders and removal of superficial skin wrinkles Synaptobrevin

25. Naturally occurring Toxins that affect Cholinergic Neurotransmission • Tetanus toxin is transported up the motor neuron and into the CNS where it blocks exocytosis of neurotransmitters from inhibitory neurons. • a-latrotoxin from black widow spider venom causes unregulated release of ACh from motor neurons to cause uncontrolled muscle contraction.