Download Postsynaptic Potential

Pharmacology of Central
Nervous System
Section 1
The Functions of Neuron and
Neuroglia
General consideration
1.composition of nervous system
(1)central and peripheral nervous
systems
(2)neuron and synapse*
Neuron
The elementary functions of neuron
(1) Receive the excitations or inhibitions
induced by internal or external stimulations.
(2)Analyze and integrate the information from
every organs.
Neuron
The elementary functions of neuron
(3)Generate or carry the demands regulating
the activities of the effectors.
(4)Some neurons have neuroendocrine function.
Neurons have 4 important zones
• Soma and dendrites –
receive the
information,generate and
integrate the local
potential changes.
• Initial segment - action
potentials are generated.
Neurons have 4 important zones
• Axon process –
transmits the
impulses to the nerve
endings.
• Nerve endings
- release the
synaptic
transmitters.
•
•
•
•
•
Neurotrophin
Nerve growth factor(NGF)
Brain-derived neurotrophin factor(BDNF)
Neurotrophin 3
Neurotrophin 4/5
Neurotrophin 6
• Ciliary neurotrophin factor(CNTF)
• Glial cell-derived neurotrophin factor(GDNF)
• Insulin-like growth factorⅠ(IGF-Ⅰ)
• Transforming growth factor(TGF)
Neuroglia
 About 1.0×1012~ 5.0×1012 neuroglia cells ,
10~50 fold of neurons
 Dendrites and axons can not be distinguished
clearly
 No synapse formed and no AP produced
The types of glial
CNS -
astrocyte
oligodendrocyte
microglia
Functions of glial cells
 Astrocytes (Astroglia)
- Support the neurons
- Clean up brain "debris"( damaged material)
and fill in the damaged area
- Transport nutrients to neurons
Functions of glial cells
 Astrocytes (Astroglia)
- regulate the external chemical environment of
neurons by removing excess ions
and recycling neurotransmitters.
 Oligodendrocytes
- myelinated axons
(1) insulate the axons
(2) facilitate the conduction of electrical impulses.
 Microglia
- act as the immune cells of the CNS
- remove most of the waste and cellular
debris from the CNS
- derivation,action in brain injury, action
in other diseases.
Section 2
General interactions
between neurons
Typical Synapses (chemical synapses)
Synapse
The small gap or space
between the axon terminals of
one neuron and the dendrites
or cell body of the next
neuron is called the Synapse .
Structure of Synapse
• Membrane of
presynaptic neuron
• Synaptic cleft
• Membrane of
postsynaptic neuron
Major types of Synapses
C
B
A
A: axo-somatic synapse
B：axo-dendritic
synapse
C：axo-axonic synapse
Classifications of Synapses
– Chemical synapses
▪Directed synapses (Typical synapses)
▪Non- directed synapses (Varicosity)
– Electrical synapses
Typical Synapses (chemical synapses)
Synapse
Process of Typical Synaptic Transmission
Process of Typical Synaptic Transmission
1. An arriving action potential
depolarizes the presynaptic
membrane.
2. Calcium ions enter the
cytoplasma of the synaptic knob
3. Neurotransmitters release.
Process of Typical Synaptic Transmission
4. Neurotransmitters diffuse to
and bind to the receptors on
postsynaptic membrane.
Process of Typical Synaptic Transmission
5. Receptors on the postsynaptic
membrane are activated,
producing a postsynaptic
potential.
6. Neurotransmitters are broken
down.
Electrical Activities of Postsynaptic
Neurons (Postsynaptic Potential)
Forms of the postsynaptic potential
• Excitatory postsynaptic potential
(EPSP)
• Inhibitory postsynaptic potential
(IPSP)
Postsynaptic Potentials
Excitatory
postsynaptic potential
Inhibitory postsynaptic potential
Postsynaptic Potentials
•When a neuron responds to the
neurotransmitter postsynaptically,
it allows ions to move across its
membrane.
Postsynaptic Potentials
•The movement of ions changes the
membrane potential of the
postsynaptic neuron.
•It is called the “postsynaptic
potential”.
EPSP
EPSP
• Excitatory transmitters → Synaptic cleft
→
bind to receptors → ↑the postsynaptic
membrane's permeability to Na+, Ca2+ →
enter the postsynaptic neuron →produce a
depolarizing potential.
IPSP
IPSP
• Inhibitatory transmitters → Synaptic cleft → bind
to receptors →  the postsynaptic membrane’s
permeability to Cl-（or K+ ） → Cl- enter the
postsynaptic neuron →generate a hyperpolarizing
potential.
• The EPSP is produced by
depolarization of the postsynaptic
membrane.
• During this potential, the
excitability of the neuron to other
stimuli is increased,
• This the potential is called the
EPSP.
• The IPSP is produced by
hyperpolarization of the
postsynaptic membrane.
• During this potential, the excitability
of the neuron to other stimuli is
decreased,
• This the potential is called the IPSP.
Neurotransmitters
40
Neurotransmitters
 Noradrenaline (NA)
 Dopamine (DA)
 5-HT (5-hydroxytryptamine)
monoamines
 Acetylcholine (ACh)
 Glutamate
 GABA (γ-aminobutyric acid)
amino acids
41
Common features of
neurotransmitters
 Synthesis
 Storage & release
 Interaction with target cell
 Termination of action
42
Synthesis -enzymes
precursor uptake
synthetic enzymes
Neurotransmitters are
synthesised from
precursors by the action
of enzymes
e.g. DA synthesised from
tyrosine by tyrosine
hydroxylase and DOPA
decarboxylase
43
Storage of transmitters- vesicles
storage
vesicles
Neurotransmitters are stored
in vesicles
Protected from metabolic
enzymes
Ready for release
44
Release of transmitter-exocytosis
Depolarization of the
terminal causes Ca++
dependent exocytosis
Action potential
exocytosis
• Voltage sensitive Ca++
channels open
• Vesicles fuse with
presynaptic membrane
and empty into synaptic
cleft
45
Interaction with target cell receptors**
Presynaptic
neurone
Post-synaptic
neurone
46
Termination of action-reuptake
Monoamines & amino acids
High affinity reuptake
removes transmitter
from the synaptic
cleft
Metabolic
enzymes
47
Termination of action- metabolism
Acetylcholine
Extraneuronal
metabolism
inactivates transmitter
choline is recycled
Metabolic
enzyme
48
Interaction with target cell-receptors
Presynaptic
neurone
Post-synaptic
neurone
Receptors
Excitatory/inhibitory
Ligand-gated ion channel
G-protein linked
49
Neurotransmitters and receptors
(1) Neurotransmitter
 Identification of neurotransmitter
Synthesis in ?
Stored in terminal and can be released
Binding to ?
Removed quickly after action
(2) Receptor
 Concept
agonist, antagonist
specific，saturation，reversible
 Classification and mechanisms
a. ion channel coupling receptor
b. metabotropic receptor (G-protein
coupled receptor)
Ligand-gated ion channels
ion channel
ION
Allosteric change
opens channel
Ions can enter
(or leave) cell
52
Ligand-gated ion channels
• Receptor with binding site linked
directly to an ion channel
• Binding to the receptor opens the
channel
• Channels are ion selective
• Ions enter or leave the cell
altering membrane potential
53
Ligand-gated ion channels
NMDA (glutamate)
Ach
5-HT3
GABAA
Na+ (Ca++) channels
excitatory
Cl- channel
inhibitory
54
G-protein linked receptors
Ions
+/-
G
Changes in
excitability
Cellular effects
G
G +/- Enzyme
Second messengers (cAMP, PI)
Calcium
release
Protein
phosphorylation
Other
55
G-protein linked receptors
• Receptor in which binding site is linked
to a G protein
• Binding to the receptor
activates enzymes  ‘second messengers’
opens ion channels
• Effects are slow and often modulatory
56
Neurotransmitters
Acetylcholine
• first compound to be identified
pharmacologically as a transmitter
in the CNS.
• Most CNS responses to acetylcholine
are mediated by a large family of G
protein-coupled muscarinic
receptors
neostriatum
A number of pathways contain medial septal
nucleus
acetylcholine
the
reticular
formation
• Cholinergic pathways
play an important role in cognitive
functions, especially memory.
Amino acid and receptor
Excitatory：glutamate，
Inhibitory：GABA ，glycine
Amino acid and receptor
a. Glu
in cerebral cortex and sensory
afferents
receptor：① ionotropic receptor：
KA，AMPA，NMDA
② metabotropic receptor
Glutamate
• Excitatory synaptic transmission is
mediated by glutamate, which is present
in very high concentrations in excitatory
synaptic vesicles .
• Glutamate is released into the synaptic
cleft by Ca2+-dependent exocytosis.
Glutamate
• The released glutamate acts on
postsynaptic glutamate receptors
• Cleared by glutamate transporters
present on surrounding glia.
Glutamate
• In glia, glutamate is converted to
glutamine by glutamine synthetase
• Released from the glia,
• taken up by the nerve terminal,
• converted back to glutamate by the
enzyme glutaminase.
Glutamate
• The high concentration of glutamate in
synaptic vesicles is achieved by the
vesicular glutamate transporter
(VGLUT).
• The ionotropic receptors divided
into three subtypes :
amino-3-hydroxy-5-methylisoxazole-4propionic acid (AMPA)
• kainic acid (KA)
• N -methyl-D -aspartate (NMDA).
• A typical excitatory synapse contains
AMPA receptors, which tend to be
located toward the periphery,
• NMDA receptors, which are
concentrated in the center.
• Kainate receptors
• Kainate receptors being expressed at
high levels in the hippocampus,
cerebellum, and spinal cord
b. GABA
in cerebral cortex and cerebrum corpus
striatum
Receptor
GABAA（ionotropic receptor）
permeability for Cl-↑
GABAB（G-protein coupled receptor）:
permeability for K+↑and for Ca2+↓
• GABA pathways:
The cerebellum - lateral vestibular nucleus;
Striatum – substantia nigra
c. Glycine
in Renshaw cell of
spinal cord but
excitatory when combine with NMDA
receptor
Receptor（ionotropic ）：permeability for
Cl ↑
Dopamine
Four pathway of dopaminergic
neurotransmission
1.limbic system- mesencephalic
pathway emotion
2.cortico- mesencephalic pathway
thinking and motion
Four pathway of dopaminergic
neurotransmission
3.nigrostriatum pathway motion
4.hypothalamo-hypophysis pathway
endocrine
• DA receptor and neural illness
• (1) DA of the substantia nigra striatum
pathways can result in Parkinson's disease;
• (2) D2 receptor of limbic systemmesencephalic pathway and corticomesencephalic pathway can lead to
schizophrenia.
 5-hydroxytryptamine, 5-HT
distribution：
raph nucleus in the middle of lower brain
stem
Receptor：5-HT1～７receptor
5 - HT :
• to participate in the activities of
cardiovascular
• awakening - a sleep cycle
• pain
• mental emotional activities
• the regulation of the hypothalamus pituitary neuroendocrine activity.
 Peptide and receptor
a. Piptide hormone in hypothalamus
b. Opium：
β-endorphin
μ
enkephalin
δ
dynorphin
κ
c. Brain-gut peptide
d. Cholecystokinin
Other transmitters
①
②
③
④
Histamin： located in hypothalamus
NO
CO
Prostaglandin
4.Mechanism of drugs on CNS
(1)axon:
slow/block axonal electrical
conduction
e.g. antiepileptics
anaesthetics
4.mechanism of drugs on CNS
(2)synapse: most drugs
①affect transmitter:
synthesis, storage, release,
reuptake.
e.g. antidepressants
4.mechanism of drugs on CNS
(2)synapse: most drugs
②affect receptor:
activation/inhibition(block)
e.g. benzodiazepines,
antipsychotics
③directly act on ion channels
e.g. phenytoin
5.BBB
(1) Structure
barrier between blood and brain cell;
3 parts barrier between blood and cerebrospinal
fluid
barrier between brain cell and cerebrospinal
fluid.
(2)function:
restrict passage of polar
compounds and macromolecules
from blood into brain
(3)Pharmacological significance: prerequisite
e.g. penicillin----meningitis
•
SUMMARY
Activity of neuron(conduction of nervous
impulse)
(1) neurotransmitter:
①NA, ACh, DA, GABA, glutamate,
glycine, 5HT, histamine, opioid
peptides,
(excitatory/ inhibitory).
②biosynthesis, storage, release,
degradation, reuptake.*
(2)receptor *
(3)conduction of impulse cross synapse:
presynaptic neuron
release neurotransmitter
synaptic cleft
neurotransmitter interacts with receptor
neurotransmitter-receptor complex initiates a
sequence of events (open ion channel)
modulate the electrical activity of the
postsynaptic neuron (depolarization/
hyperpolarization). *