Autonomic Nervous System Overview

Nomenclature

• The Parasympathetic Nervous System (PSNS) is also called:
  • Cholinergic
  • Muscarinic
• The Sympathetic Nervous System (SNS) is also called:
  • Adrenergic

Anatomy

• PSNS Nerves (Craniosacral):
  • Originate from the top and bottom of the spinal cord
• SNS Nerves (Thoracolumbar):
  • Originate from the middle of the spinal cord

ANS Anatomy

• The SNS and PSNS both have ganglia
• The neurotransmitter released at the ganglia is acetylcholine (ACh)
• The receptors in the ganglia are nicotinic receptors

Neurotransmitters (NT)

• Acetylcholine is synthesized from Acetyl CoA and Choline
• Acetylcholine is stored in synaptic vesicles

ANS Anatomy - The Adrenal Medulla:

• The adrenal medulla is source of NT, releasing 80% epinephrine (Epi) and 20% norepinephrine (NE)

Neurotransmitters (NT): Synthesis

• Key NT like dopamine, norepinephrine, and epinephrine are synthesized from tyrosine
• The catecholamines (dopamine, norepinephrine, epinephrine) are a type of NT synthesized from tyrosine

Receptor Distribution: Cholinergic

• There are two types of cholinergic receptors: Nicotinic and Muscarinic
• Nicotinic receptors are found in:
  • Muscle
  • Ganglia
  • Adrenal Medulla
  • Central Nervous System (CNS)
  • Immune System
• Muscarinic receptors are divided into 5 subtypes:
  • M1, M3, M5: G-protein coupled (Gq)
  • M2, M4: G-protein coupled (Gi)

PSNS-Receptors

• PSNS Receptors are referred to as Muscarinic (M)
• Most drugs targeting M receptors are not classified by subtype
• Fewer drugs target M receptors than adrenergic receptors
• M receptors play an important role in drug side effects

M1, M3, M5 Receptors

• G-protein coupled (Gq)
• Found in:
  • Smooth Muscle:
    • Contraction
  • Bladder:
    • Contraction

M2, M4 Receptors

• G-protein coupled (Gi)
• Found in:
  • Heart:
    • Decreased rate, contraction
    • Decreased heart rate

PSNS-Receptors

• The effects of muscarinic agonists oppose the effects of adrenergic agonists
• Effects of muscarinic agonists:
  • Heart:
    • Decreased rate
    • Decreased contraction
  • Lungs:
    • Bronchoconstriction
  • Sphincters (GI and bladder):
    • Relaxation
  • Walls:
    • Contraction of bladder and GI tract walls

To Pee or Not to Pee - Bladder and Urination

• PSNS response in the bladder:
  • M3 in bladder wall: contracts
  • M3 in sphincter: relaxes
  • This results in urination

PSNS-Receptors

• Increased secretion:
  • Salivary
  • Respiratory
  • Tears
• Eye: (more on this later)

PSNS-Receptors

• M receptors play an important role in CNS
• M Receptors are important for cognitive function

Ligands for Muscarinic Receptors

• Direct stimulation:
  • Use of an agonist
• Indirect stimulation:
  • Acetylcholinesterase inhibitors increase the concentration of acetylcholine

Indirect-Acting Cholinergic Drugs

• Cholinesterase can bind to 3 types:
  • Acetylation:
    • Rapid Recovery
    • Physiological
  • Carbamylation:
    • Slower Recovery
    • Reversible drugs (e.g., neostigmine)
  • Phosphorylation:
    • No recovery
    • Irreversible drugs (e.g., "nerve gases")

Indirect-Acting Cholinergic Drugs:

• Irreversible cholinesterase inhibitors have been used in chemical warfare

Excess Cholinergic Response

• Excessive cholinergic response can cause:
  • Excessive secretion
  • Other related side-effects

Alpha-1 Adrenergic Receptors

• G-protein coupled (Gq)
• Causes contraction

Sympathetic Nervous System (SNS)

• Alpha-2 (α-2)
  • Function: inhibits the release of norepinephrine

Alpha-2 Agonists

• Binding of alpha-2 receptor agonist:
  • Inhibits the release of norepinephrine

Sympathetic Nervous System (SNS)

• Beta-1 (β-1)
  • Function: stimulates the heart
  • Location:
    • Heart:
      • Increased heart rate
      • Increased atrioventricular conduction
      • Increased contractility

Beta-1 Adrenergic Receptors

• G-protein coupled (Gs)
• Found in:
  • Heart:
    • Increased heart rate
    • Increased contractility

Beta-1 Adrenergic Receptors

• Liver, kidney, and uterus are innervated by the SNS
• Kidney:
  • Beta-1 receptors stimulate renin release
  • Renin causes increased blood pressure

Beta-2 Adrenergic Receptors

• Function: relaxation of smooth muscle
• Location:
  • Lungs: Bronchodilation
  • Blood vessels in skeletal muscle: Vasodilation
  • GI tract, bladder, uterus: relaxation of walls

Beta-2 Adrenergic Receptors

• G-protein coupled (Gs)
• Found in:
  • Lungs: Bronchodilation

To Pee or Not to Pee - Bladder & Urination

• SNS response in the bladder:
  • β-2 in bladder wall: relaxes
  • α-1 in sphincter: contracts
  • This results in not urinating

Beta-2 Adrenergic Receptors

• Liver, kidney, and uterus innervated by the SNS
• Liver:
  • Beta-2 receptors mediate glucose release by:
    • Gluconeogenesis: formation of new glucose
    • Glycogenolysis: breakdown of glycogen to glucose

Ligands for Adrenergic Receptors

• Sympathomimetics mimic stimulation of the SNS:
  • Direct activation of adrenergic receptors
  • Increased NT in the synapse

Sympathomimetics

• Increasing NT in the synapse by:
  • Increasing neurotransmitter release
  • Inhibiting reuptake of neurotransmitter

Fate of Neurotransmitters

• Reuptake pumps sit presynaptically, remove neurotransmitters from the synapse

Sympathomimetics

• Inhibiting neurotransmitter reuptake increases the amount of NT in the synapse

Sympathomimetics

• Increasing NT in the synapse:
  • Inhibiting neurotransmitter reuptake is more effective
  • Muscarinic antagonists can also be used
  • Beta-2 agonists can also be used, but have minimal effect

Case #2

• A compound causes the following:
  • Skeletal muscle vessels to relax
  • Uterus relaxation
  • Bronchodilation
• This compound is likely a beta-2 agonist

ANS effects in the circulation (Summary/Review)

• SNS:
  • β-2 receptors (skeletal muscle): Vasodilation
  • α-1 receptors: Vasoconstriction
• PSNS:
  • Minimal contribution to circulation
  • Stimulation of M3 causes nitric oxide release, leading to vasodilation

Case #2

• A compound causes the following:
  • Skeletal muscle vessels to relax
  • Bladder wall relaxation
  • Bronchodilation
• This compound is likely a beta-2 agonist

ANS Effects in the Bladder (Summary/Review)

• SNS:
  • β-2 receptors (bladder wall): Relaxation
  • a-1 receptors (sphincter): Contraction
  • Result: Do not pee
• PSNS:
  • M3 in bladder wall: Contraction
  • M3 in sphincter: Relaxation
  • Result: Pee