• ANS Anatomy
  • Autonomic and Somatic Innervation
  • Autonomic Reflex Arc
  • Autonomic Reflex Arc: First Link
  • Sensory Fiber Neurotransmitter(s)
  • Autonomic Nervous System Neurotransmitters: Summary
  • CNS and the Autonomic Nervous System
    • Spinal Cord Reflexes
    • Hypothalamus and Nucleus tractus solitarii
    • Higher Centers
  • Peripheral ANS Divisions
• Comparison between Sympathetic & Parasympathetic Systems
• Sympathetic Nervous System Anatomy
  • Diagram Sympathetic System
  • Anatomical Outline
    • Paravertebral Ganglia
    • Prevertebral Ganglia
    • Terminal Ganglia
    • Adrenal Medulla
• Parasympathetic System Anatomy
• ANS Neurotransmitter Effector Organs

• Interactions between Sympathetic & Parasympathetic Systems
• "Fight or Flight": Characteristics of the ANS

• ANS Neurotransmission
  • Neurotransmitter Criteria
  • Neurotransmission Steps:
    • Axonal Conduction
    • Storage and Release of Neurotransmitter
    • Combination of Neurotransmitter and Post-Junctional Receptors
    • Termination of Neurotransmitter Action
    • Other Non-electrogenic Functions
  • Cholinergic Neurotransmission
    • Transmitter Synthesis and Degradation
    • Acetylcholinesterase
    • Acetylcholine: Storage and Release
    • Site Differences:
      • Skeletal Muscle
      • Autonomic Effectors
      • Autonomic Ganglia
      • Blood vessels
    • Signal Transduction: Receptors
• Adrenergic Transmitters: Biosynthetic Pathways
• Adrenergic Neurotransmission: Introduction to the Neurotransmitters
• Catecholamine Synthesis, Storage, Release and Reuptake
  • Enzymes
  • Catecholamine storage
  • Regulation of adrenal medullary catecholamine levels
  • Reuptake
  • Metabolic Transformation
  • Indirect-acting sympathomimetics
  • Release
• Adrenergic Receptor Subtypes
  • ß-adrenergic receptors
  • Alpha-adrenergic receptors
  • Catecholamine Refractoriness
• Other Autonomic Neurotransmitters
  • Co-transmission
    • ATP
    • VIP
    • Neuropeptide Y family
  • Purines
  • Nitric Oxide (Modulator)
• Predominant Sympathetic/Parasympathetic Tone
• Baroreceptor Reflexes
• Pharmacological Modification of Autonomic Function
• Autonomic Dysfunction

To support the idea that a chemical is a neurotransmitter, several conditions must be satisfied:

1.  The chemical should be found in the appropriate anatomical location (e.g. synaptic terminal)
2.  Enzymes that are involved in "transmitter" synthesis should also be present.
3.  Where possible (as in autonomic transmission), recovery of the "transmitter" in higher quantities following nerve stimulation than in the absence of stimulation.*
4.  Externally applied (e.g. iontophoretically applied) chemical produces the same effect as stimulation. For example, the reversal potential is the same.
5.  Effects of antagonists influence the response to externally applied chemical in the same manner as antagonists modify responses following nerve stimulation.

* may not be possible in many instances

• Depolarization of the axonal membrane potential results in an action potential.
• The upstoke of the action potential is a sodium current flowing through voltage-activated sodium channels
• As the membrane potential decreases, activation occurs of an outgoing potassium current, which opposes further depolarization and initiates repolarization.
• Longitudinal spread of local depolarizing sodium currents results in progressive, longitudinal activation of sodium channels and new sites of depolarization. The rate of conduction is dependent on the number and synchrony of sodium channel activation.
• Number and synchrony of sodium channel activation is membrane potential dependent.
  • As the resting membrane potential decrease (towards 0), fewer sodium channels will be activated by a depolarizing influence and conduction velocity slows.
• In myelinated fibers, depolarization occurs at the Nodes of Ranvier.

• Small molecule neurotransmitters (e.g. acetylcholine, norepinephrine) are synthesized at axonal terminals and stored in synaptic vesicles

"The electron micrograph shows synaptic vesicles, purified from rat brain (negative staining, courtesy of Dr. Peter R. Maycox). Each is about 50 nm in diameter (1/20,000th of a millimeter). The inset shows a few vesicles labeled by immunogold for one of the major synaptic vesicle proteins (synaptophysin)."--Research group of Reinhard Jahn (http://www.mpibpc.gwdg.de/abteilungen/190/sv.html)

• "Synaptic vesicles belong to the most abundant organelles in the body. 

  • The human CNS contains about 10¹¹ neurons. Each of these neuron forms on average about 1000 synapses, and each synapse contains about 500 vesicles, resulting in more than 10¹⁷ synaptic vesicles. 

  • This is more than eight magnitudes more than the human genome has base pairs! 

  • Synaptic vesicles can be purified in high yields to high degrees of purity, allowing for their biochemical characterization. Presently, synaptic vesicles are probably the best characterized organelles. 

  • They contain a limited number of proteins that in many cases were discovered as the prototype of small protein families with a widespread distribution on trafficking organelles. 

  • According to our current estimates, the majority of all vesicle-associated proteins are known. The vesicle proteins can be divided into two groups according to their function: the trafficking proteins and the proteins involved in neurotransmitter uptake and storage.

    •  The first group includes proteins of diverse structure such as synaptobrevin/VAMP (involved in exocytotic membrane fusion), synaptotagmin (the exocytotic Ca²⁺-sensor), rab proteins (probably mediators of protein assembly required for membrane fusion) and several proteins of unknown function that contain four transmembrane domains (synaptophysins, synaptogyrins, SCAMPs). 

    • The second group includes the neurotransmitter transporters, the vacuolar proton ATPase, and probably ion channels required for compensatory charge equilibration." ---Research group of Reinhard Jahn

• Isolated neurotransmitter "quanta", perhaps corresponding to single vesicle neurotransmitter quantity, is randomly released in the basal state. This level of release, generating miniature end-plate potentials (mepp's), is necessary for resting skeletal muscle tone.

• Action Potentials, promoting calcium influx, induce large, synchronous release of several hundred quanta . Calcium facilitates vesicular membrane-synaptic membrane fusion, resulting in vesicular content discharge into the synaptic cleft.

• Many chemical can inhibit norepinephrine or acetylcholine release through receptor interactions at the appropriate terminal. Examples:

• Neurotransmitter diffuses across the synaptic cleft and bind to post-junctional receptors causing an increase in membrane conductance (ions flow)

• If the EPSP is of sufficient magnitude to cause the membrane potential to reach the threshold potential, an action potential results (e.g. in skeletal or cardiac muscle). In gland cells an EPSP may cause secretion; in other cells, an EPSP may increase the rate of spontaneous depolarization.
• An IPSP (produced in neurons and smooth, but not skeletal muscle) opposes EPSPs.

EPSP: excitatory postsynaptic potential; IPSP: inhibitory postsynaptic potential

• Cholinergic: Termination of action of acetylcholine is acetylcholine hydrolysis. (acetylcholinesterase-catalazed)
  • If acetylcholinesterase is inhibited, the duration of cholinergic effect is increased.
• Adrenergic: Termination of action of adrenergic neurotransmitters is by reuptake and diffusion away from receptors.
• Amino Acids: Termination of action of amino-acid neurotransmitters is by active transport into neurons and glia

• Basal, quantal release of transmitter in quantities insufficient to generate an EPSP may have other actions. These effects may include:
  • regulation of neurotransmitter biosynthetic and degradative enzymes
  • pre- and post-synaptic receptor density

• Acetylcholine is synthesized from the immediate precursors acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase (choline acetylase).

• Rapid inactivation of acetylcholine is mediated by acetylcholinesterase.
• Acetylcholinesterase is present at ganglia, visceral neuroeffector junctions, and neuromuscular junctional endplates.
• Another type of cholinesterase, called pseudo-cholinesterase or butyrylcholinesterase has limited presence in neurons, but is present in glia. Most pseudocholinesterase activity is found in plasma and liver.
• Pharmacological effects of anti-cholinesterase drugs are due to inhibition of acetylcholinesterase.

• Small random release of acetylcholine-quanta, producing miniature end-plate potentials (mepps) , are released by presynaptic terminals.
  • These small currents were linked to ACh release since anticholinesterases (neostigmine) increased their effects, while cholinergic receptor antagonist (tubocurarine, a nicotinic receptor blocker) blocked.
• Anatomical counterpart to the electrophysiological quanta is the synaptic vesicle.
• The model is based on the nicotinic, skeletal neuromusclar junction.
• Synchronous exocytotic release of many more quanta, dependent on Ca²⁺ occur when an action potential reaches the terminal.
• Exocytotic release of acetylcholine and other neurotransmitters is inhibited by toxins elaborated by Clostridium botulinum.

• Neurotransmitter: Acetylcholine
• Receptor Type: Nicotinic
• Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:
  • an enhanced post-synaptic responsiveness, denervation hypersensitivity.
    • Denervation hypersensivity in skeletal muscle is due to
      1. increased expression of nicotinic cholinergic receptors
      2. and their spread to regions aways from the endplate.

• Neurotransmitter: Acetylcholine
• Receptor type: Muscarinic
• effector coupled to receptor by a G protein
• In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.
  • Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.
• Acetylcholine decreases heart rate by decreasing the rate of  SA nodal pacemaker phase 4 depolarization.

• Neurotransmitter: Acetylcholine
• Receptor type: Nicotinic
• Generally similar to skeletal muscle site: initial depolarization is due to receptor activation. The receptor is a ligand-gated channel.

• Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).
• In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.