Medical Pharmacology: Autonomic Nervous System Pharmacology

Medical Pharmacology Chapter 4: Autonomic (ANS) Pharmacology: Introduction

Neurotransmitters and the Autonomic Nervous System
- Neurotransmitter Criteria: 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
- Neurotransmission Steps
  - Axonal conduction
    - 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.
  - Synaptic (Junctional) Activity
  - Storage and Release of Neurotransmitter
    - Small molecule neurotransmitters (e.g. acetylcholine, norepinephrine) are synthesized at axonal terminals and stored in synaptic vesicles

Synaptic vesicles (electron micrograph)

"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 "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.

"Chemical Synapse Animation"

Attribution: Twedt R Gala R Chemical Synapse Animation https://www.youtube.com/watch?v=mItV4rC57kM (12/2013) retwedt Youtube Channel: https://www.youtube.com/channel/UCSjnM-g6fxSbQ-WQ3EfwEVw

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:
1. Norepinephrine + presynaptic α₂-adrenergic receptor (autoreceptor) inhibits norepinephrine release
2. α₂ receptor antagonists increase release of norepinephrine
3. Neurally-mediated acetylcholine release from cholinergic neurons is inhibited by α₂-adrenergic receptor agonists
4. Stimulation of presynaptic β₂ adrenergic receptors increases slightly norepinephrine release
These agents inhibit neurally-mediated norepinephrine released by interacting with presynaptic receptors
- Adenosine
- Acetylcholine
- Dopamine
- Prostaglandins
- Enkephalins
Neurotransmitter + Post-Junctional Receptors Interactions Lead to Physiological Response
- Neurotransmitter diffuses across the synaptic cleft and bind to post-junctional receptors causing an increase in membrane conductance (ions flow)
- Three primary types of changes in conductance may occur:
  - Increase in Na⁺ (usually) or Ca⁺ conductance which depolarizes the membrane (EPSP)
  - Increase in Cl^- permeability: inward hyperpolarizing flow : membrane potential more negative) (IPSP)
  - Increase in K⁺ permeability; K⁺ leaves the cells, resulting in hyperpolarization, (IPSP)
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.
Definitions: EPSP: excitatory postsynaptic potential; IPSP: inhibitory postsynaptic potential.
Termination of Transmitter Action
- 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.
Other Nonelectrogenic Functions
- 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.