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Pharmacology – II [PHL 322]
The basic principles of central
synaptic neurotransmission
Dr. Abdulaziz Saad Bin
Saeedan
Introduction
• SYNAPTIC TRANSMISSION
• The
communication
between
two
nerve
cells.
Communication believed to involve specialized structures
termed "synapses".
• Charles Sherrington (1897) : named ‘Synapse’
Neuron structure
All
neurons
have
same
basic
structure, a cell body with a number
of dendrites and one long axon.
Neuron
• Axons carry information from the cell body to the axon terminals.
• Axon terminals communicate with their target cells at synapses.
Types of Synapses
• CNS Synapses
•
Axodendritic: Axon to dendrite
•
Axoaxonic: Axon to axon
•
Axosomatic: Axon to cell body
•
Dendrodendritic: Dendrite to
dendrite
Signal transmission in neurons
Principles of Synaptic Transmission
• Basic Steps
• Neurotransmitter synthesis
• Load neurotransmitter into synaptic vesicles
• Vesicles fuse to presynaptic terminal
• Neurotransmitter spills into synaptic cleft
• Binds to postsynaptic receptors
• Biochemical/Electrical response elicited in postsynaptic
cell
• Removal of neurotransmitter from synaptic cleft
• Must happen RAPIDLY!
Principles of Synaptic Transmission
• Neurotransmitters: “substance that is released at a synapse by
one neuron and that affects a postsynaptic cell, in a specific
manner”
• Amino acids
• Amines
• Peptides
Principles of Synaptic Transmission
• Neurotransmitters
• Small molecules synthesized in the terminal button and
packaged in synaptic vesicles. E.g. Amino acids and
amines are stored in synaptic vesicles
• Large molecules assembled in the cell body, packaged in
vesicles, and then transported to the axon terminal. E.g.
Peptides are stored in and released from secretory granules
 Often coexist in the same axon terminals
Principles of Synaptic Transmission
• Neurotransmitter Synthesis and Storage
Principles of Synaptic Transmission
• Release of Neurotransmitter (NT) Molecules :
• Exocytosis – the process of NT release
• A nerve impulse reaches the terminal knob of a neuron, causing the presynaptic membrane to depolarize.
• The depolarization of the pre-synaptic membrane causes voltage gatedcalcium-channels to open.
• The entry of Ca2+ causes vesicles to fuse with the terminal membrane
and release their contents
Principles of Synaptic Transmission
• Neurotransmitter Release
• Secretory granules
 Released from membranes that are away from the active
zones
 Requires high-frequency trains of action potentials to be
released
Principles of Synaptic Transmission
• Neurotransmitter receptors: There are multiple receptor types
for a given NT
• Ionotropic: Transmitter-gated ion channels
 Ligand-binding causes a slight conformational change that leads to the
opening of channels
 Depending on the ions that can pass through, channels are excitatory
or inhibitory
 NT binds and an associated ion channel opens or closes, causing a PSP.
If Na+ channels are opened, an EPSP occurs. If K+ channels are
opened, an IPSP occurs
Excitatory and Inhibitory Postsynaptic Potentials:
• EPSP: Transient postsynaptic membrane depolarization by presynaptic
release of neurotransmitter. E.g. Ach- and glutamate-gated channels cause
EPSPs
• IPSP: Transient hyperpolarization of postsynaptic membrane potential
caused by presynaptic release of neurotransmitter. E.g. Glycine- and GABAgated channels cause IPSPs
OUT
Cl-
Na+
Cl-
Na+
GABAA receptor
Inhibition
IN
Glutamate/AMPA
receptor
Excitation
Principles of Synaptic Transmission
• Metabotropic: G-protein-coupled receptors
 Trigger slower, longer-lasting and more diverse postsynaptic actions
 Same neurotransmitter could exert different actions depending on what receptors
it bind to
 (1) NT 1st messenger binds. (2) G protein subunit breaks away. (3) Ion channel
opened/closed OR a 2nd messenger is synthesized. (3) 2nd messengers may have
a wide variety of effects.
Effector proteins
• Autoreceptors: present on the presynaptic terminal
 Typically, G-protein coupled receptors
 Commonly, inhibit the release or synthesis of neurotransmitter
 Negative feedback
Principles of Synaptic Transmission
• Neurotransmitter Reuptake, Enzymatic Degradation, and
Recycling
• As long as NT is in the synapse, it is active – activity must
somehow be turned off
• Clearing of neurotransmitter is necessary for the next round
of synaptic transmission
 Simple Diffusion
 Reuptake aids the diffusion
 Neurotransmitter re-enters presynaptic axon terminal or enters
glial cells through transporter proteins
 Enzymatic destruction
 In the synaptic cleft
 Acetylcholinesterase (AchE)
Principles of Synaptic Transmission
• Neuropharmacology
• The study of effect of drugs on nervous system tissue
• Receptor agonists: Mimic actions of naturally occurring
neurotransmitters
 E.g. Nicotine binds and activates the Ach receptors of skeletal muscle
(nicotinic Ach receptors)
• Receptor antagonists: Inhibitors of neurotransmitter receptors
 e.g. Curare binds tightly to Ach receptors of skeletal muscle, causing
weakness of muscles
DOPAMINE
• D1, D2, D3, D4, D5 receptors; all metabotropic
• D1, D5: all postsynaptic, and increase adenylate cyclase (AC)
• D2, D3, D4: presynaptic and postsynaptic, and decrease AC
Dopamine pathways do many things:
• Control flow of blood through the brain
• Motor control (nigrostriatal) system
• Behavioural control: Dopamine is the brain’s motivational
chemical. The primary role of dopamine is pleasure and motivation.
A shortage of brain dopamine causes an indecisive
personality, unable to initiate even the body’s own movement
(Parkinson’s disease).
Excess dopamine, more excitement. Attention deficit
disorder. May cause schizophrenia.
Neurotransmitters and Neuromodulators
• Catecholamines synthesized from tyrosine
• Indoleamines synthesized from tryptophan
Catecholamine biosynthesis
indoleamine biosynthesis
SEROTONIN
- At least 14 different receptor subtypes
- 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F; all metabotropic
- 5-HT2A, 5-HT2B, 5-HT2C; all metabotropic
- 5-HT3; ionotropic, Cl- channel, inhibitory input
- 5-HT1B and 5-HT1D are presynaptic autoreceptors
A synapse that uses serotonin/5-HT
Fluoxetine/Prozac blocks the SERT
Re-uptake of 5-HT/serotonin
Treatment of depression.
anxiety disorders,
obsessive-compulsive disorders
5–hydroxytryptamine (Serotonin)
Functions :
1. Addiction, aggression, anxiety, impulsivity
2. Learning, memory, mood
3. Emesis, nausea, appetite
4. Penile erection, sexual behavior
5. Sleep,
6. Thermoregulation
7. Respiration
8. Vasoconstriction
9. movement
Deficiencies in the Function of Serotonin
Anxiety, depression, obsessive-compulsive disorder, schizophrenia,
stroke, obesity, pain, hypertension, vascular disorders, migraine, and
nausea to disruptions and particularly deficiencies of serotonin.
5–hydroxytryptamine (Serotonin)
Clinical uses :
1. Antidepressants & anxiolytics
2. Atypical antipsychotics:
3. Anorectics (decreases appetite): releases 5HT
4. Antiemetics :
5. Gastroprokinetic agents:
6. Antimigraine agents
7. Increases appetite: 5-HT2A blocker
Glutamate
• Excitatory neurotransmitter
• Located – throughout CNS
• Receptor types
a) Ionotropic receptors
i) NMDA – long duration of action (Ca+ Channel)
ii) AMPA – fast action (Na+ Channel)
iii) Kainic acid – fast action (Na+ Channel)
b) Metabotropic (GPCR) receptors: autoreceptor
Glutamate – clinical use
1.
Alzheimers disease, influenza
2.
Cough suppressant
3.
Anesthesia
4.
Stroke
5.
Epilepsy
6.
Diabetic neuropathic pain
7.
Senile dementia
8.
Suppress withdrawal symptoms from morphine
Gama Amino Butyric Acid (GABA)
• Synthesized from glutamic acid by GAD
• Actions Major inhibitory neurotransmitter (NT)
• Location – Widely distributed in brain & spinal cord
• Receptor types & actions –
a) GABAA
- Ionotropic, Cl- influx, postsynaptic receptor
- fast IPSP
b) GABAB
- Metabotropic, GPCR,
- K+ activate channel , reduce Ca2+
conductance, inhibit adenyl cyclase
- slow & long lasting IPSP
c) GABAC
- Cl- influx
Clinical uses – GABA related drugs
1. As antiepileptics
2. As anesthetics
3. Sedative hypnotics ( BZD, barbiturates) in case of:
- anxiety
- insomnia
- sedation & amnesia
- component of anesthesia
- control of ethanol or sedative-hypnotic withdrawal state
- muscle relaxants
4. Migraine headache prophylaxis – - valproate, topiramate
5. Spasmolytics :stroke, cerebral palsy, multiple sclerosis
- baclofen, diazepam
Thanks