Physiology

of the
Neuron
Generalities
In order to understand the effects of drugs on the CNS,
the structure and function of the neuron (the nerve
cell) is essential
The neuron is the basic component of the CNS
Neurons have special characteristics that distinguish
them from other cells
A Can conduct electrical impulses over long
distances
B Carry out specific input and output relations
with other cells and other tissues of the body
Generalities
These input/output connections determine the
functions of a particular neuron and therefore the
behavioral response that neuronal activity may elicit
The typical neuron consists of:
OSoma (the cell body)
ODendrites (zillions of branched extensions)
OAxon (an elongated nerve bundle)
O**Synapse (the microspace between neurons)
** Not considered to be a structure
Introduction
Research regarding the electrical activity of the neuron
was originally conducted using the giant axon of the
squid
The axon of the squid measures up to a millimeter in
diameter and is 100 times larger than the axon of human
nerve cells
The squids axon is used to contract muscles that squirt
water out of the squids body, thereby propelling it
through the body
Resting Potential
Neurons have a charge across their membranes
(electrical)
If the charge is measured by an oscilloscope and the
charge is left undisturbed, this charge will remain
relatively constant at about -70 millivolts (mV)
This charge is called the RESTI NG POTENTI AL
The Resting Potential
0
-70
-Time (milliseconds)
Resting Potential
Salt is NaCl
LNa is positively charged, therefore called
Na
+
LCl is negatively charged, therefore called Cl
-
Resting Potential
If you put salt into a glass of water it would dissolve into
Na
+
and Cl
-
Inequalities in the concentration of the ions in different
places would cause the ions to flow down their
concentration gradient until they are equally distributed
Inequalities in the charges would cause the the ions to
flow down their electrostatic gradient
Therefore, the concentration AND the charge of sodium
and chloride will be equal everywhere and so will the
Cell Membrane
Intracellular compartment is inside
Extracellular compartment is outside
Ions present:
An
-
- Negatively charged organic compounds
Cl
-
- Negatively charged Clorine
K
+
- Positively charged Potassium
Na
+
- Positively charged Sodium
Depolarization
When the transmembrane voltage decreases toward 0 mV,
the membrane is said to have become depolarized
Depolarization is thought to be due to increased inward
movement of Na
+
ions
The NA
+
gates open when the membrane is depolarized
Hyperpolarization
When the transmembrane voltage increases, the
membrane is said to have become hyperpolarized
Hyperpolarization is thought to be due to increased
outward movement of K
+
ions or an increased inward
movement of Cl
-
ions
Cell Membrane
The four charged ions would be present in equal amounts
on both sides of the membrane if it did not act as a
barrier to their passage
The membranes act as a barrier in three ways:
An
-
- Too large to pass through the membrane -
therefore retained in the intracellular fluid
CThe membrane is semipermeable to Na
+
, K
+
, and
Cl
-
; each of these has its own channel through
which it passes
CThe membrane contains a pumping system - also
called the sodium-potassium pump, which
exchanges intracellular Na
+
for extracellular K
+
Action Potential
The neurons membrane undergoes a dramatic change if
stimulation is intense enough to cause the transmembrane
voltage to depolarize to about -50 mV
At the voltage of -50 mV the membrane becomes
completely permeable to Na
+
Na
+
rushes into the cell until the voltage across the
membrane falls to 0 mV
The Na
+
channel then closes
At the same time the membrane also becomes permeable
to K
+
ions which flow outside the cell to balance the
inward flow of Na
+
Action Potential
The voltage at which the membrane undergoes this
change is called the threshold
The sudden reversal of polarity and the restoration of the
resting potential is called the Action Potential
What triggers the action potential?
The ion conductance through the channels for NA
+
are
controlled by gates
These gates are sensitive to voltage
The Nerve Impulse
When an action potential occurs, it opens up the voltage-
sensitive Na
+
channels
The action potential that occurs at one end of an axon will
travel along the length of that axon - these usually occur
at the cell body and travel away from it
The traveling of this action potential is termed the nerve
impulse
The Nerve Impulse
The nerve impulse speed increases as the resistance to the
impulse decreases (daaaahhh!!!)
Large axons conduct at a faster rate than the small ones
Glial cells are used to speed impulse propagation
Shwann cells in the peripheral nervous system and
oligodendroglia cells in the CNS wrap around some
axons, forming a myelin sheath (myelin in Greek means
marrow)
The Nerve Impulse
Gaps in the myelin (between glial cells) are called Nodes
of Ranvier
Impulses, therefore, jump along the axon from node to
node called saltatory conduction
Saltatory conduction is an extremely efficient way of
speeding the impulse because a small myelinated axon
can conduct an impulse as rapidly as an unmyelinated
axon 30 times as large
Axon
Electrical impulses:
OOriginate in the dendrite
OIntegrated in the soma
OTransmitted down the axon to the synapse
Axon
OVaries in length from a few millimeters
to as long as a meter
OSome project down the spinal cord and run from
motor neurons to the muscles they innervate
OTransmits activity from the soma to other
neurons or muscles, organs, or glands
OUsually conducts impulses in one direction
Electrical Impulse
Electrical impulses:
OFrom the soma
ODown the axon
OTo a specialized structure that together with
the dendrites from another neuron, form a
complex microstructure called a synapse
Synapse
Small space between the presynaptic membrane (on
the axon terminal) of one neuron and the postsynaptic
membrane (usually found on the dendrite)
The presynaptic terminal contains numerous structural
elements, the most important of which are small
synaptic vesicles
These vesicles store several thousands of molecules of
neurotransmitter chemicals
These vesicles, therefore, store the transmitter which
is available for release
Synapse
Exocytosis - The process of exocytosis is where
molecules of neurotransmitter are released into the
synaptic cleft
The transmitter substance diffuses across the synaptic
cleft and attaches to receptors on the dendrite of the
next neuron
The process of transmitting information across the
synaptic cleft, from one neuron to another, is one of a
chemical nature
Because neurons do not touch each other, synaptic
transmission is a chemical rather than an electrical
process
The Neuron
Usually only one axon arises from the soma
The projections from the soma give rise to many side
branches
These side branches send impulses to hundreds or
thousands of other neurons
The Neuron
Remember that the dendrite partly consists of the post-
synaptic terminal membrane
These side branches send impulses to hundreds or
thousands of other neurons - this is known as
divergence of information
The dendrites branch profusely and receive several
thousand contacts from other cells - this results in
what is called convergence of information
The Neuron
The dendrites then process the information and
passively transmit electrical activity to the soma
The soma actively transmit the impulses down the
axon to as many as 10,000 other neurons
Thus, thousands of neurons converge on a single
neuron, which, in turn, spreads its own impulses to
thousands of other neurons
The Neuron
Neurons tend to group together and form circuits
The areas in the brain where cell bodies congregate
are called nuclei
Bundles of axons that project from one group of
neurons to another are called fiber tracts
In the peripheral nervous system, these fiber tracts are
called nerves
The sciatic nerve is actually a bundle of axons, the
somas of which are located in the spinal cord (motor
neurons), the dorsal root ganglia (sensory neurons), or
autonomic ganglia
The Neuron
In the brain, nuclei tend to congregate to form yet
larger structures
OThalamus
OHypothalamus
OAmygdala
OHyppocampus
Review: The neuron consists of three basic elements
ODendrites
OSoma
OAxon

Electrical impulses (review):
OOriginate in the dendrites
OAre integrated in the soma
OAre transmitted down the axon to the synapse
The Axon
The axon is specialized solely for the reliable
conduction of electrical activity
All action potentials are conducted down a given axon
rapidly and without alteration
The only way to change content of information
relayed by an axon is to alter the number of action
potentials that are conducted each second
The axon is not a site of action for psychoactive drugs
The axon is the site of action for local anesthetics
The local anesthetic blocks the propagation of
impulses down the axon - synaptic processes are not
involved
The Dendrite
The distal terminals of the axon align themselves at
the synapse with one or more of the dendrites or the
soma of the next neuron
Dendrites contain receptors that are sensitive to
transmitter released from other neurons
The Dendrite
Order of steps in the transmission of a nerve impulse
(this is general - specific will come later)
OAn impulse is conducted down an axon of a neuron
OA chemical transmitter is released into the synapse
OThe receptors on the dendrite of the postsynaptic
neuron exhibit an electrical charge
The magnitude of the electrical charge that
crosses the synapse is proportional to the
amount of the chemical transmitter that is
released (implications for drug therapy)
The Soma
The dendrites and soma receive input from other
neurons through synapses
These dendrites and soma respond by becoming either
depolarized or hyperpolarized
The effect of the depolarization or hyperpolarization is
reflected in the excitability of the soma
The Soma
If the influence of the excitatory synapses is greater
than the influence of the inhibitory synapses, the soma
responds by producing an action potential that is
propagated through its axon and conducted to the next
synapse
If the influence of the inhibitory synapses is greater
than the influence of the excitatory synapses, the soma
hyperpolarizes and the neuron becomes less excitable
Steps in Synaptic Transmission
There are about a dozen
steps in the synaptic
transmission process - each
one constitutes a possible
site of drug action
Acetylcholine
Acetylcholine is a neurotransmitter found in large
amounts in the brain
H
3
C C S CoA
O
Acetyl-CoA
+ H
3
C N
+
CH
2
CH
2
OH
CH
3
CH
3
Choline
Choline
Acetylase
H
3
C N
+
CH
2
CH
2
O
CH
3
CH
3
Acetylcholine
C CH
3
O
+
HS CoA
Coenzyme A
Acetylcholine
After acetylcholine is synthesized, it is stored in the
nerve terminal within synaptic vesicles
It is released into the synaptic cleft when an action
potential arrives from the axon
AcH then diffuses across the cleft and attaches itself to
postsynaptic receptors
Note: Scopolamine is a psychedelic drug that blocks
postsynaptic receptors for AcH - this causes impulses
to continue across the cleft and the effects of a
psychedelic drug
Acetylcholine
There are two types of AcH receptors on the
postsynaptic dendritic membrane
OA nicotinic receptor (a ligand-gated ion channel)
OA muscarinic receptor (is part of a seven helix
family)
At the postsynaptic receptor (on the dendrite) the
action of AcH is terminated when the enzyme
acetylcholine esterase (AChE) destroys it
Acetylcholine
The enzyme reaction that destroys AcH is important as
there are many drugs that inhibit this enzyme called
AChE inhibitors
This results in continuing passing of impulses across
synapses
These drugs, AChE inhibitors, are used in agriculture
as insecticides
Also used in the military as lethal nerve gasses
Acetylcholine
AcH postsynaptic dendritic receptors are largely
absent in patients with Alzheimer's disease - therefore
the tremor which is the results of persisting impulses
across neural clefts that are not opposed by
Acetylcholine Esterase
These drugs, AChE inhibitors, are used in agriculture
as insecticides
Also used in the military as lethal nerve gasses
Acetylcholine
Acetylcholine secreting neurons are located in the
hyppocampus and cerebral cortex and may participate
in:
OLearning

OMemory function

ORetrieval of memory

OMood

OBehavioral arousal

OAttention

OEnergy conservation

OREM activity


Norepinephrine and Dopamine
The term catecholamine refers to three chemically
related compounds
OEpinephrine

ONorepinephrine

ODopamine

Epinephrine (adrenaline) is found mainly in the
peripheral nervous system and works to maintain
blood pressure and heart rate - not commonly found in
the brain
Norepinephrine and Dopamine
Norepinephrine and dopamine are the primary
catecholamine neurotransmitters in the brain
Many drugs that profoundly affect brain function and
behavior exert their effects by altering the synaptic
action of norepinephrine and dopamine in the brain
Drugs that alter behavior probably produce their
effects because they alter the chemical transmission
between neurons
Norepinephrine and Dopamine
Note: Patients with Parkinsons disease exhibit a level
of dopamine in the caudate nucleus that is lower than
the amount normally present
Administration of dopamine does not work as
dopamine does not cross the blood-brain barrier
The administration of Dopa, the precursor to
dopamine, does cross the blood brain barrier, where it
is converted to dopamine
Therefore, the chemical synthesis of a transmitter may
be used for clinical benefit
HO CH
2
CH NH
2
COOH
Tyrosine Tyrosine hydrolase
HO CH
2
CH NH
2
HO
Dopa
dopa decarboxylase
COOH
HO CH
2
CH NH
2
HO
Dopamine
dopamine b-hydroxylase
HO CH
2
CH NH
2
HO
Norepinephrine
COO
H
Norepinephrine and Dopamine
Metabolic fate of norepinephrine and dopamine
A transmitter is synthesized (produced), stored (in
vesicles), exerts its postsynaptic effect, and then
inactivated
Inactivation occurs by either of two processes
OEnzymatic destruction of the transmitter within the
synaptic cleft
OActive reuptake of the transmitter from the synaptic
cleft back into the presynaptic nerve terminal
Norepinephrine and Dopamine
Catecholamines are inactivated by two enzymes
OMonoamine oxidase (MAO)
OCatechol O-methyltransferase (COMT)
OMonoamine oxidase (MAO)
OCatechol O-methyltransferase (COMT)
This inactivation process by these two enzymes is
slow and does not account for rapid termination of
either norepinephrine or dopamine
The postsynaptic effects of these two transmitters are
terminated primarily by an active process (that
requires energy) of reuptake across the presynaptic
nerve membrane back into the nerve endings
This way, these two transmitters are stored again in the
synaptic vesicles and reused later
Norepinephrine and Dopamine
The principle of reuptake into the nerve terminal and
then into the storage vesicles is critically important
because certain drugs may block:
OThe active uptake process into the nerve terminal
(thus prolonging the synaptic action of the
transmitter)
OThe uptake of the transmitter from the intracellular
fluid in the nerve terminal back into the synaptic
vesicles (this decreasing the amount of the stored
transmitter available for release)
Norepinephrine and Dopamine
Cocaine - blocks presynaptic reuptake of dopamine
from the synaptic cleft into the nerve terminal
resulting in prolonged synaptic action or stimulation
(therefore not allowing the dopamine to re-enter the
intracellular fluid then go back into the vesicle)
Tricyclic antidepressants are drugs that block
presynaptic reuptake into the nerve terminals of
norepinephrine
Reserpine blocks the uptake of the transmitter back
into the vesicle (resulting in depression, mood swings,
etc)
Norepinephrine and Dopamine
The dynamics of dopamine and norepinephrine
resemble those of other CNS transmitters - those
previously described
The Norepinephrine synapse is very similar to the
acetylcholine terminal
Norepinephrine and Dopamine
The presynaptic terminal contains mitochondria and
small vesicles that contain stored transmitter
The vesicles contain chemicals that are different from
the acetylcholine terminal
They contain the amino acid tyrosine (from food)
Tyrosine is taken up into the presynaptic terminal,
where it is transformed into dopa, dopamine, and then
norepinephrine
In the terminals where the enzyme beta-hydroxylase is
not present, dopamine isnt converted into
norepinephrine, and dopamine serves as the
transmitter
HO CH
2
CH NH
2
COOH
Tyrosine Tyrosine hydrolase
HO CH
2
CH NH
2
HO
Dopa
dopa decarboxylase
COOH
HO CH
2
CH NH
2
HO
Dopamine
dopamine b-hydroxylase
HO CH
2
CH NH
2
HO
Norepinephrine
COOH
Norepinephrine and Dopamine
After synthesis (after the transmitter is produced or
manufactured) it is stored in the presynaptic vesicles
An action potential arrives
There is a brief influx of calcium
The transmitter is released by exocytosis from the
vesicles
The transmitter enters the synaptic cleft
Transmitter diffuses across the cleft and attaches to the
postsynaptic receptors
Process terminates with reuptake of the transmitter
into the nerve (presynaptic) terminal
Norepinephrine Pathways
The cell bodies of the norepinephrine neurons are
located in the brain stem
From the brain stem the axons project into the nerve
terminals of:
OThe cerebral cortex
OThe limbic system
OThe hypothalamus
OAnd the cerebellum
Norepinephrine Pathways
The release of norepinephrine produces:
OMood altering
OFocusing
OOrienting (fight/flight/fright response)
OPositive feeling of reward
OAnalgesia
OHunger
OThirst
OEmotion
OSex
Messengers
Remember this:
OFirst Messenger - this is the neurotransmitter
OSecond Messenger - this is the post-syanptic
membrane substance
Dopamine Pathways
Large amounts of dopamine are found in the basal
ganglia, frontal cortex, and limbic system
The originating cell bodies of these nerve terminals
are found in the substantia nigra
Examples of dopamine function involve schizophrenia
and parkinsonism
Schizophrenics show increase dopamine synthesis in
the frontal cortex - therefore this disease is treated
with dopamine blocking agents
Parkinson's - no dopamine receptors (receptor
agonists) found in the substantia nigra
Dopamine Pathways
Phenothiazine drugs, as an expression of toxicity, and
show Parkinson-like signs; due to blockade of
dopamine receptors in the frontal cortex
Parkinsonism is treated with drugs that stimulate the
production of dopamine
The behavioral stimulant and reinforcing properties of
cocaine and amphetamine reflect activation of
dopamine receptors
Serotonin
Is a neurotransmitter
Is an inhibitor of activity and behavior
Functions in
OSleep
OWakefulness
OMood
OTemperature regulation
OFeeding
OSexual activity
Amino Acids
In order to understand how the CNS depressants work,
it is necessary to understand how the transmission of
impulses across nerve ending occur
Four amino acids function as neuronal transmitters
OGlutamic acid
OAspartic acid
Excite neuronal transmission
OGABA
OGlycine
Inhibit neuronal
transmission
**GABA = gamma-aminobutyric acid
Amino Acids
GABA is the major inhibitor of neurotransmission in
the brain
When GABA receptors are stimulated by the presence
of GABA, they typically inhibit the post-synaptic
neuron from firing
Amino Acids
Many classes of drugs can bind to various sites on the
GABA receptor, enhancing GABA-mediated
inhibition
OBenzodiazepines
OBarbiturates
OAnesthetics
OSteroids
OAlcohol
Amino Acids
Probably all neurons of the CNS have GABA
receptors embedded in their cell bodies, dendrites, and
axon endings
Many classes of drugs can bind to various sites on the
GABA receptor, enhancing GABA-mediated
inhibition
OBenzodiazepines
OBarbiturates
OAnesthetics
OSteroids
OAlcohol
Amino Acids
Virtually every neuron in the CNS is responsive to
GABA
When GABA receptors are activated, chloride
permeability increases, thus hyperpolarizing the
affected membrane
When the receptor becomes hyperpolarized resulting
an increase in Cl
-
permeability, this is termed a
GABA
A
receptor
A second type of GABA receptor is one whose
activation opens channels to K
+
or Ca
+
= GABA
B
Amino Acids
GABA
A
receptors are ligand-gated ion channels with
multiple binding sites
GABA
B
receptors are G-protein-coupled receptors
GABA
GABA comes from (is synthesized by) the amino
acid glutamate via the enzyme glutamic acid
decarboxylase
C OH
O
CH
2
CH
2
C
O
OH
H
C
NH
2
glutamic acid
decarboxylase
H
CH
2
CH
2
C
O
OH
H
C
NH
2
GABA
After GABA is synthesized (remember GABA is a
neurosynaptic transmitter) it is stored for release
After GABA is released it acts on both the presynaptic
and postsynaptic GABA
A
and GABA
B
receptors
The action of GABA is terminated by reuptake from
the synaptic cleft
GABA
REMEMBER and DONT FORGET - GABA is the
major inhibitor of neurotransmission in the brain
Drugs that facilitate GABAergic (promoters)
neurotransmission produce results that demonstrate
the inhibitory effect of this neurotransmitter
OSedation

OReduced vigilance

OSleep

OReduced emotional reactivity

OAmnesia

OMuscle relaxation


Opioid Receptors
In the 1960s it was proposed that chemicals exist in
the brain that provide analgesia (relief of pain) by
acting on specific receptors and that opioid narcotics
might mimic these natural analgesic substances by
binding the same receptors
In 1973 opioid receptors were identified in the CNS
In 1976 four types of opioid receptors were identified
OMu OKappa
ODelta OSigma
Opioid Receptors
The question was whether there were substances in the
brain that acted like opioids
Crude extracts were taken from the brain that
demonstrated an ability to stop intestinal peristalsis (a
morphine like action)- which, get this, could be
blocked by naloxone (a drug used to stop opiate
action)
Opioid Receptors
Two proteins were isolated from these extracts called:
OMet-enkephalin OLeu-enkephalin
Later, a protein was identified in the pituitary gland
+Beta-lipotran
This pituitary protein contained met-enkephalin