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Chapter 07
The Nervous
System
Part 2
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IV. Acetylcholine
Acetylcholine (ACh)

ACh is a neurotransmitter that directly opens ion
channels when it binds to its receptor.
 In some cases, ACh is excitatory, and in other
cases it is inhibitory, depending on the organ
involved
 Excitatory in some areas of the CNS, in some
autonomic motor neurons, and in all somatic
motor neurons
 Inhibitory in some autonomic motor neurons
Two Types of Acetylcholine Receptors

Nicotinic ACh receptors
1) Can be stimulated by nicotine
2) Found on the motor end plate of skeletal
muscle cells, in autonomic ganglia, and in some
parts of the CNS
 Muscarinic ACh receptors
1) Can be stimulated by muscarine (from
poisonous mushrooms)
2) Found in CNS and plasma membrane of
smooth and cardiac muscles and glands
innervated by autonomic motor neurons
Agonists and Antagonists
1) Agonists: drugs that can stimulate a receptor
a) Nicotine for nicotinic ACh receptors
b) Muscarine for muscarinic ACh receptors
2) Antagonists: drugs that inhibit a receptor
a) Atropine is an antagonist for muscarinic
receptors.
b) Curare is an antagonist for nicotinic receptors.
Chemically Regulated Channels

Binding of a neurotransmitter to a receptor can
open an ion channel in one of two ways:
1. Ligand-gated channels
2. G-protein coupled channels
Ligand-Gated Channels

The receptor protein is also an ion channel;
binding of the neurotransmitter directly opens the
ion channel.
 Nicotinic ACh receptors are ligand-gated channels
with two receptor sites for two AChs.
 Binding of 2 acetylcholine molecules opens a
channel that allows both Na+ and K+ passage.
1) Na+ flows in, and K+ flows out.
2) Due to electrochemical gradient, more Na+
flows in than K+ out.
Nicotinic ACh Receptors
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Extracellular Fluid
1. Channel closed until
neurotransmitter
binds to it
Binding
site
Ion
channel
Na+
2. Open channel
permits diffusion of
specific ions
Acetylcholine
Plasma
membrane
(a)
Nicotinic ACh
receptors
Cytoplasm
K+
(b)
Ligand-gated channels

Inward flow of Na+ depolarizes the cell, creating
an EPSP (excitatory postsynaptic potential).
1) EPSPs occur in the dendrites and cell bodies.
2) EPSPs from the binding of several ACh
molecules can be added together to produce
greater depolarization  summation of
graded-potentials
3) This may reach the threshold for voltage-gated
channels in the axon hillock, leading to action
potential.
Graded nature of EPSPs
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mV
Cell bodies
and dendrites
Axon
Membrane
potential
+30
Action potential
EPSPs
Threshold
–50
rmp
–70
Time
Relative amounts of
excitatory neurotransmitter
Comparison of EPSPs and Action Potentials
G-Protein Coupled Channels




Ligand-gated channels that do not directly open
ion channels
These channels are coupled to a G-protein located
on the intracellular membrane surface
Once ligand binds, G-protein separates and
attaches to a nearby ion channel.
This binding either opens or closes ion channels.

Muscarinic ACh receptors interact with ion channels
in this way as well as dopamine and norepinephrine
receptors
G-Protein Coupled Channels

Associated with a G-protein
1) G-proteins have three subunits (alpha, beta,
and gamma).
2) Binding of one acetylcholine results in the
dissociation of the G-protein subunits.
3) Either the alpha or the beta-gamma diffuses
through the membrane to bind ion channels.
4) This opens the channel for short period of time.
5) The G-protein subunits dissociate from the
channel and it closes
Steps in the activation and deactivation
of G-proteins
G-protein Coupled Channels
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ACh
K+
1. ACh binds
to receptor
Plasma membrane
β
α
γ
Receptor
G-proteins
2. G-protein
subunit
dissociates
β
γ
3. G-protein
binds to K+
channel,
causing it
to open
K+
K+ channel
G-protein couple channels

Binding of acetylcholine opens K+ channels in
some tissues (IPSP) or closes K+ channels in
others (EPSP).
1) In the heart, K+ channels are opened by the
beta-gamma complex, creating IPSPs
(hyperpolarization) that slow the heart rate.
2) In the smooth muscles of the stomach, K+
channels are closed by the alpha subunit,
producing EPSPs (depolarization) and the
contraction of these muscles.
Acetylcholinesterase (AChE)


AChE is an enzyme that inactivates ACh activity
shortly after it binds to the receptor.
Hydrolyzes ACh into acetate and choline, which
are taken back into the presynaptic cell for reuse.
Action of Acetylcholinesterase (AChE)
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Presynaptic axon
Presynaptic axon
Acetylcholine
Acetate
Choline
Acetylcholinesterase
Receptor
Postsynaptic cell
Postsynaptic
cell
ACh in the PNS

Somatic motor neurons form interactions called
neuromuscular junctions with muscle cells.
 The area on the muscle cell with receptors for
neurotransmitter is called the motor end plate.
a. EPSPs formed here are often called end plate
potentials.
b. End plate potentials open voltage-gated Na+
channels, which result in an action potential.
c. This produces muscle contraction
Interruption of Neuromuscular Transmission

Certain drugs can block neuromuscular
transmission.
 Curare is an antagonist of acetylcholine. It blocks
ACh receptors so muscles do not contract.
1) Leads to paralysis and death (due to paralyzed
diaphragm)
 Used clinically as a muscle relaxant
Drugs that Affect the Neural Control of
Skeletal Muscles
Alzheimer Disease

Associated with loss of cholinergic neurons that
synapse on the areas of the brain responsible for
memory
V. Monoamines as
Neurotransmitters
Introduction

Monoamines are regulatory molecules derived
from amino acids
 Catecholamines: derived from tyrosine; include
dopamine, norepinephrine, and epinephrine
 Serotonin: derived from L-tryptophan
 Histamine: derived from histidine
Monoamine Action and Inactivation


Like ACh, monoamines are made in the
presynaptic axon, released via exocytosis, diffuse
across the synapse, and bind to specific receptors.
They are quickly taken back into the presynaptic
cell (called reuptake) and degraded by
monoamine oxidase (MAO).
Monoamine Action and Inactivation
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Presynaptic
neuron ending
1. Monoamine produced and
stored in synaptic vesicles
Action
potentials
Tyrosine
Ca2+
Dopa
2. Action potentials open
gated Ca2+ channels,
leading to release of
neurotransmitter
Dopamine
5. Inactivation of most
neurotransmitter by MAO
Priming
Norepinephrine
Fusion
4. Reuptake of most
neurotransmitter
from synaptic cleft
3. Neurotransmitters
enter synaptic cleft
Norepinephrine
Receptor
Postsynaptic
cell
Monoamine Action



None of the receptors for these signals are direct
ion channels.
All use a second messenger system.
Cyclic adenosine monophosphate (cAMP) is the
most common second messenger for
catecholamines.
Monoamine Action



Binding of a catecholamine to its receptor activates
a G-protein to dissociate and send the alpha
subunit to an enzyme called adenylate cyclase
which converts ATP to cAMP
cAMP activates an enzyme called protein kinase,
which phosphorylates other proteins.
An ion channel opens.
Norepinephrine Action & G-proteins
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1. Norepinephrine
binds to its
receptor
Norepinephrine
Adenylate cyclase
Ion channel
Plasma membrane
Receptor
α
β
G-proteins
α
α
γ
2. G-protein
subunits
dissociate
3. Adenylate
cyclase
activated
ATP
Opens
ion channels
cyclic AMP
Protein kinase
(inactive)
Postsynaptic cell
Protein kinase
(active)
Phosphorylates
proteins
4. cAMP activates protein
kinase, which opens ion
channels
Serotonin as a neurotransmitter

Used by neurons in the raphe nuclei (middle
region of brain stem)
 Implicated in mood, behavior, appetite, and
cerebral circulation
 The drug LSD and other hallucinogenic drugs
may be agonists.
 Serotonin specific reuptake inhibitors (SSRIs)
are used to treat depression.
1) Prozac, Paxil, Zoloft
Serotonin


Over a dozen known receptors allow for diversity
of serotonin function.
Different drugs that target specific serotonin
receptors could be given for anxiety, appetite
control, and migraine headaches.
Dopamine as a neurotransmitter

Neurons that use dopamine (dopaminergic
neurons) are highly concentrated in the midbrain in
two main areas:
a. Nigrostriatal dopamine system: involved in
motor control
b. Mesolimbic dopamine system: involved in
emotional reward
Nigrostriatal Dopamine System

Neurons from the substantia nigra (part of the
basal nuclei) of the brain send dopaminergic
neurons to the basal nuclei (caudate nucleus,
putamen, globus pallidus).
 Important step in the control and initiation of
movements
 Parkinson disease is caused by degeneration of
these neurons.
 Patients are treated with L-dopa and MAOIs
(monoamine oxidase inhibitors).
Mesolimbic Dopamine System



Regions of the midbrain send dopaminergic
neurons to regions of the forebrain.
Involved in emotional reward systems and
associated with addictions such as nicotine,
alcohol, and other drugs
Schizophrenia is associated with too much
dopamine in this system.
 Drugs that treat schizophrenia are dopamine
antagonists.
Norepinephrine as a neurotransmitter




Used in both the CNS and PNS
Sympathetic neurons of the PNS use
norepinephrine on smooth muscles, cardiac
muscles, and glands.
Used by neurons of the CNS in brain regions
associated with arousal
Amphetamines work by stimulating norepinephrine
pathways in the brain.
VI. Other Neurotransmitters
Amino acids as NTs

Excitatory NT – glutamate
 An amino acid used as the major excitatory
neurotransmitter in the brain
 Produces EPSPs in 80% of the synapses in the
cerebral cortex
 Energy required for all the EPSPs constitutes
the major energy use in the brain
 Astrocytes take glutamate from the synaptic
cleft to increase glucose uptake and increase
blood flow by vasodilation
Glutamate Receptors


All glutamate receptors also serve as ion channels
a) NMDA receptors
b) AMPA receptors
c) Kainate receptors
NMDA and AMPA receptors work together in
memory storage.
Inhibitory NTs

Glycine
 Amino acid used as a neurotransmitter to
produce IPSPs
 Binding of glycine opens Cl− channels, causing
an influx of Cl−.
 Makes it harder to reach threshold
 Important in the spinal cord for regulating
skeletal muscle movement. This allows
antagonistic muscle groups to relax while others
are contracting (e.g., biceps relax while triceps
contract).
Glycine

Also important in the relaxation of the diaphragm,
which is necessary for breathing
 The poison strychnine blocks glycine
receptors, which produces death by
asphyxiation.
GABA




Gamma-aminobutyric acid is the most common
neurotransmitter in the brain and is used by 1/3 of
the brain’s neurons.
It is inhibitory, opening Cl− channels when it binds
to its receptor.
It is involved in motor control.
Degeneration of GABA-secreting neurons in the
brain results in Huntington disease.
GABA receptors contain a chloride channel
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GABA
Chloride ion (Cl–)
Plasma
membrane
I
1. Channel closed
until receptor binds
to GABA
Channel
closed
GABA
receptors
3. Diffusion of Cl–
into cell causes
hyperpolarization (IPSP)
2. GABA receptor
binds to GABA, Cl–
channel opens
Polypeptides as neurotransmitters

Neuropeptides
 Many chemicals used as hormones or paracrine
signals are also found in the brain acting as
neurotransmitters.
 CCK: involved in a feeling of satiety after a
meal
 Substance P: mediates sensations of pain
Neuromodulators
1) Neurons that release a classical NT like Ach or
norepinephrine along with a polypeptide
2) Can release either under different conditions
3) Called synaptic plasticity – capacity for alteration
at the molecular level
Endogenous Opioids



Opioid receptors were discovered to bind with
drugs such as opium and morphine, resulting in
pain relief.
Endogenous opioids are polypeptides produced
by the brain and pituitary gland; includes
enkephalin, β-endorphin, and dynorphin
Opioids also produce euphoria so they may
mediate reward pathways; may be related to
feeling of well-being after exercise
Neuropeptide Y




Most abundant neuropeptide in the brain
Plays a role in stress response, circadian rhythms,
and cardiovascular control
Powerful stimulator of hunger; leptin inhibits
neuropeptide Y release to suppress appetite
Works by inhibiting the release of glutamate in the
hippocampus (excess glutamate release can
cause convulsions)
Endocannibinoids



Neurotransmitters that bind to the same receptors
that bind to the active ingredient in marijuana
(THC)
Short fatty acids produced in the dendrites and cell
bodies and released directly from the plasma
membrane (no vesicle)
Retrograde neurotransmitters released from the
postsynaptic neuron; inhibit further
neurotransmitter release from the presynaptic
axon
Endocannibinoids



Endocannibinoids can inhibit IPSP-producing
NTs from one neuron so EPSP-producing NTs
from another neuron can have a greater effect.
Endocannibinoids may enhance learning and
memory and have been shown to induce
appetite; depolarization-induced suppression of
inhibition
Marijuana use impairs learning and memory
because the action of THC is widespread and
not controlled.
Nitric Oxide and Carbon Monoxide

Nitric oxide
a. A gas produced by some neurons in the CNS
and PNS from the amino acid L-arginine
b. Diffuses across the presynaptic axon plasma
membrane (no vesicle)
c. Diffuses into the target cell and activates the
production of cGMP as a second messenger
d. Causes blood vessel dilation and helps kill
bacteria
e. May also act as a retrograde NT
Nitric Oxide

In the PNS, nitric oxide is secreted by autonomic
neurons onto cells in the digestive tract, respiratory
passages, and penis, causing muscle relaxation.
 Responsible for an erection
 The drug Viagra works by increasing NO
release.
Carbon Monoxide (CO)




Another gas used as a neurotransmitter
Derived from the conversion of heme to biliverdin
Also activates the production of cGMP in target
cells
Used in the olfactory epithelium and cerebellum
ATP & Adenosine as NTs




Used as cotransmitters released via vesicles with
another neurotransmitter
Classsified chemically as purines; bind to
purinergic receptors
a. P1 receptor for ATP
b. P2 receptor for adenosine
Released with norepinephrine to stimulate blood
vessel constriction and with ACh to stimulate
intestinal contraction
Released by nonneural cells; act as paracrine
regulators in blood clotting, taste, and pain
Chemicals that are or may be NTs
VII. Synaptic Integration
Introduction

Neural pathways
 Divergence of neural pathways: Axons have
collateral branches, so one presynaptic neuron
can form synapses with several postsynaptic
neurons.
 Convergence of neural pathways: Several
different presynaptic neurons (up to a thousand)
can synapse on one postsynaptic neuron.
Summation


Spatial summation occurs due to convergence
of signals onto a single postsynaptic neuron.
 All of the EPSPs and IPSPs are added
together at the axon hillock.
Temporal summation is due to successive
waves of neurotransmitter release that add
together at the initial segment of the axon
Spatial Summation
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1
Action potential
+30 mV
2
–55 mV
Threshold
EPSP
–70 mV
EPSP
EPSP
Release of neurotransmitter
from neuron 1 only
Release of
neurotransmitter from
neurons
and
1
2
Synaptic Plasticity


Repeated use of a neuronal pathway may
strengthen or reduce synaptic transmission in
that pathway.
When repeated stimulation enhances
excitability, it is called long-term potentiation
(LTP).
 Found in the hippocampus of the brain
where memories are stored
 Associated with insertion of AMPA
glutamate receptors
Long-term potentiation


Improves the efficacy of synaptic transmission that
favors transmission along frequently used
pathways
Seen in learning and memory in the hippocampus
Synaptic Plasticity

Long-term depression (LTD) occurs when
glutamate-releasing presynaptic neurons stimulate
the release of endocannibinoids.
 This suppresses the further release of
neurotransmitter.
 Due to removal of AMPA receptors
 Short-term (20-40 sec) is called DST,
depolarization-induced suppression of
inhibition
Synaptic plasticity

Both LTP and LTD depend on a rise in calcium ion
concentration within the postsynaptic neuron
 Rapid rise leads to LTP
 Smaller but prolonged rise leads to LTD
 Synaptic plasticity involves enlargement or
shrinkage of dendritic spines
Synaptic Inhibition


Postsynaptic inhibition is produced by inhibitory
neurotransmitters such as glycine (spinal cord)
and GABA (brain).
Hyperpolarizes the postsynaptic neuron and
makes it less likely to reach threshold voltage at
the axon hillock
Synaptic Inhibition
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1
2
–55 mV
–70 mV
Threshold for action potential
IPSP
EPSP
–85 mV
Inhibitory
neurotransmitter
from neuron 1
Excitatory
neurotransmitter
from neuron 2
Presynaptic Inhibition

Decreased in excitatory NTs being released from
one presynaptic axon through axoaxonic synapse
from another presynaptic axon
 Calcium ion channels are inactivated
 Seen in the action of endogenous opioids in
pain reduction; inhibits the release of substance
P that promotes pain transmission