THOMAS C. WESTFALL
SYNAPSE SYMPOSIUM:
PHARMACOLOGICAL PRINCIPLES OF
SYNAPTIC TRANSMISSION
OUTLINE
• Level at Which Drugs Act:
• Cellular and Molecular
• Systems
• Behavioral
• Functional Classification of Central Nervous System Signaling
Molecules
• Types of Neurotransmitters – CNS Drugs Will be Affecting
• Criteria for the Establishment of a Neurotransmitter
• Specific Examples
• Drug Sensitive Site in Synaptic Transmission
• General Classification of Drugs Acting in the CNS
• Examples that we will study in this course or one of the other
modules this year.
Table 1: The Four Levels of Drug Action and Drug Classification
Mechanism
Definition
Response Components
System
An effect on system
function
Integrated systems
including linked systems
(e.g. nervous system;
cardiovascular system,
etc.
Tissue
An effect on tissue
function
Electrogenesis;
contraction; secretion;
metabolic activity;
proliferation
Cellular
Transduction
The biochemicals linked
to the drug target (e.g.
ion channel, enzyme, Gprotein
Molecular
Interaction with the
drugs molecular target
The drug target (e.g.,
receptor; ion channel
enzyme; carrier
molecule)
Table 4: The Four Main Types of Receptors
Type 1
Type 2
Type 3
Type 4
Location
Membrane Membrane Membrane Nucleus
Effector
Channel
Enzyme or Enzyme
channel
Gene transcription
Coupling
Direct
G-Protein
Via DNA
Examples
nACh
Receptor
GAGA-A
Receptor
Adrenergic Insulin
Receptors Receptor
ANF
Receptor
Direct
Steroid/Thyroid
receptor
Functional Classification of Central Nervous
System Signaling Molecules
-Key targets for drugs
ƒNeurotransmitters
ƒNeurohormones
ƒNeuromodulators
ƒNeuromediators
ƒNeurotrophic Factors
Neurotransmitter
- Strict definition has changed through the years.
Satisfaction of the experimental criteria for identification of
synaptic transmitters can lead to the conclusion that a substance
contained in a neuron is secreted by that neuron to transmit
information to its postsynaptic target.
In some cases:
Transmitters may produce minimal effects on bioelectric
properties, yet activate or inactivate biochemical mechanisms
necessary for responses to other circuits,
--- OR --The action of the transmitter may vary with the context of
ongoing synaptic events – enhancing excitation or inhibition,
rather than operating to impose direct excitation or inhibition.
Neurohormone
Classically defined as substances originating in neurons or
neurosecretory cells, receiving synaptic information from other
central neurons yet secreting transmitters in a hormone-like fashion
into the circulation (i.e. a substance secreted into the blood from a
neuron)
However some of these neurons may also form traditional
synapses within central neurons (e.g., oxytocin; vasopressin)
KEY NEUROTRANSMITTERS
Amines
Amino Acids
Dopamine
Glutamate
Norepinephrine
Glycine
Epinephrine
γ-aminobutyric acid (GABA)
Serotonin (5HT)
Purines
Acetylcholine
ATP
Histamine
Adenosine
Gases
Nitric Oxide
Peptides
Vasopressin
Neuropeptide Y
Oxytocin
Neurotensin
Tachykinins
Opioids
Cholecystokinin
Somatostatin
Neurohormone
Classically defined as substances
originating in neurons or neurosecretory
cells, receiving synaptic information from
other central neurons yet secreting
transmitters in a hormone-like fashion into
the circulation (I.e. a substance secreted
into the blood from a neuron)
However some of these neurons may
also form traditional synapses within central
neurons (e.g., oxytocin; vasopressin)
Neuromodulator
A substance originating from neurons, or other cellular
and non-synaptic sites, yet influences the excitability of nerve
cells.
Neuromediator
Substances that participate in the elicitation of the
presynaptic or postsynaptic response to a transmitter or in the
generation of synaptic potentials and release of transmitter (e.g.,
second messengers cAMP; cGMP; phosphoinositides, etc.)
Neurotrophic Factors
Substances produced within the CNS by neurons,
astrocytes, microglia or transiently invading peripheral
inflammatory or immune cells that assist neurons in their
attempts to repair damage.
MAJOR WAYS IN WHICH DRUGS ACT
I
Non-specific CNS Depressants
II
Non-Specific CNS Stimulants
III
Selective Modifiers
Non-Specific CNS Stimulants
Act by producing blockade of inhibition or direct
neuronal excitation → increased transmitter release;
more prolonged transmitter action; labilization of the
postsynaptic membrane; decreased recovery time
EXAMPLES
Pentelenetetrazol
Some aspects of methylxanthines
Non-Specific CNS Depressants
Depress excitable tissue at all levels of the CNS →
Depression of neurotransmission and depression of
postsynaptic responsiveness
EXAMPLES
Anesthetic gases
Aliphatic alcohols
Some Sedative-Hypnotic Drugs
Selective modifiers of CNS Function
MOST IMPROTANT and LARGEST GROUP may
cause excitation, inhibition or both of neuronal function.
Examples:
y Anti-convulsants
y Anti-Parkinson Drugs
y Opioid and non-opioid analgesics
y Appetite suppressants
y Anti-emetics
y Analgesic-antipyretics
y Certain stimulants or depressants
y Anti-manic
y Anti-anxiety
y Anti-psychotics
y Sedative-hypnotics
y Hallucinogens