Neurotransmitters &

Neuromodulators

Concepts you should

already know before this
lecture

Cell membrane ion channels

Resting membrane potential
Local potential
Temporal summation
Spatial summation
Action potential
EPSP
IPSP

Types of Synapses in the

CNS

Presynaptic Inhibition
and Facilitation
Axoaxonic synapses mediate
presynaptic inhibition and facilitation,
e.g. present in the spinal cord to
regulate the propagation of
information to the brain.
Interneurons regulate the ability of the
presynaptic neurons to release
neurotransmitters by changing the
amount of Ca++ influx to the
presynaptic neurons.

Electrical vs. Chemical

Synapse

http://www.ncbi.nlm.nih.gov/books/NBK11164/

Type

Electrical

Chemical

Length of
3.5 nm
synaptic
cleft
Cytoplasmi Yes
c continuity
Structure
Gap junction

20-40 nm

Agents of
transmissio
n
Synaptic
delay

Ion current
(electrical)

Neurotransmitt
ers (chemical)

Virtually
absent

> 1-5 ms

No
Presynaptic
vesicles
Postsynaptic
receptors

Chemical Synapse

Dobrunz,
2002

Synaptic Communication
Total # of action potentials reaching the
presynaptic terminal directly influences
the amount of neurotransmitter released
excitatory stimuli to the presynaptic
neuron cause increased # action
potentials reaching the presynaptic
terminal
duration of excitatory stimuli to the
presynaptic neuron cause a longer
series of action potentials reaching the
presynaptic terminal

NEUROTRANSMITTERS
AND NEUROMODULATORS

What is a
Neurotransmitter?

It is synthesized in the neuron

It is present in the presynaptic terminal
It is released in amounts sufficient to
exert an action on the postsynaptic
neuron or effector organ
It is removed from the synaptic cleft by
a specific mechanism
Synaptic vesicle cycling
http://neuroscience.uth.tmc.edu/s1/ch
apter05.html
Schwartz, 2005

What is a
Neurotransmitter?
When administered exogenously (e.g.
drugs) in reasonable concentration, it
mimics the action of the endogenously
released neurotransmitter exactly. It
activates the same ion channels or
second messenger system in the
postsynaptic cell.
Some define neurotransmitters to
include neuromodulators that act away
from the synaptic cleft (Blumefeld, 2010).
Schwartz,

What is a
Neuromodulator?

Act at a distance away from the synapse

Modulate activity of many neurons
Released into extracellular fluid
The same chemical substance can act
either as a neurotransmitter or
neuromodulator
Effects last minutes to days
Neurotransmitters and neuromodulators
can be released simultaneously

Functions of
Neurotransmitters

Mediate communication between neurons

or the end-organs through fast excitatory
(EPSP) or inhibitory (IPSI) postsynaptic
potentials (<1 ms)
Directly opening ligand-gated ion
channels on postsynaptic membrane
Slow-acting neuromodulation, occurring
over 100ms to minutes
Indirect opening ion channels or
activation the cellular signaling cascades

Neurotransmitter
Receptors
Receptors are often named according
to the neurotransmitters to which they
bind, e.g. GABAA, GABAB, 5-HT receptors
The same neurotransmitter may bind
to several types of receptors, e.g.
Serotonin
The effect of neurotransmitters on a
postsynaptic neuron is determined by
the type of receptors present on its
membrane, e.g. Ach, Norepinephrine

Signal Transmission
Mechanisms: Direct
Activation of Ion
Channels
Neurotransmitters
bind to receptors that
are part of the ligandgated ion channels
and directly open the
ion channels.

Signal Transmission
Mechanisms: Indirect
Activation of Ion
Channels
Neurotransmitters
bind to receptors that
are separate from the
ion channels, and
indirectly open the ion
channels by activating
the G-protein. This
process involves
changes in the
metabolism of the cell.

Signal Transmission
Mechanisms: Activating
Intracellular Signaling
Activation of the Gprotein secondmessenger system
can trigger the
intracellular signaling
cascade. This process
has long lasting
effects on regulating
genes expression and
neuronal growth.
Byrne, 1997

Termination of Synaptic
Transmission
Removing neurotransmitters
Diffusion: remove a fraction only
Enzymatic degradation: e.g.
acetylcholinesterase
Reuptake: most common, e.g. serotonin
Desensitizing receptors by
Receptor internalization: folding the
postsynaptic membrane containing the
receptors into the cell
Receptor inactivation

Common
Neurotransmitters and
Neuromodulators

Amino Acid
GABA
Glutamate
(Glu)
Glycine (Gly)
Cholinergic
Acetycholine
(ACh)

Amine
Dopamine (DA)
Serotonin (5HT)
Norepinephrin
e (NE)
Peptide
Substance P
Endorphins

Amino Acid: GABA

Fast-acting MAJOR inhibitory
neurotransmitter found in the entire CNS,
e.g. inhibitory interneurons in spinal cord
Prevents excessive neural activity
Barbiturates mimics the action of GABA
and are used for sedation, as
anticonvulsants.
Baclofen, a muscle relaxant to control
muscle spasticity, increases presynaptic
release of GABA

Amino Acid: Glutamate

(Glu)

Fast-acting MAJOR excitatory

neurotransmitter found in the entire CNS
Involved in learning and memory
Glutamate is present in a wide variety of
foods, e.g. MSG
Overactivity of glutamate may cause
seizures
Excitotoxicity: Excessive glutamate may
produce neuronal damage or death, e.g.
TBI or CVA (X1000 higher than normal)

Glutamate Receptors
AMPA: ligand gated receptor
NMDA: ligand- and voltage-gated receptor
Postsynaptic neuron must depolarize
when the Glu binds to the NMDA
receptor in order to open the gate
Prolonged opening of ion channels
resulting in long-term potentiation (LTP)
Metabotropic glutamate receptor: indirect
activation by G-protein pathway

Acetylcholine (ACh)
MAJOR neurotransmitters in PNS, ANS
Fast-acting effect: act at neuromuscular
junction, e.g. Nicotinic receptors
Slow-acting effect: regulate HR, ANS
function, e.g. Muscarinic receptors
Primary as a neuromodulator in CNS
Controls locomotion, arousal
Facilitate attention, memory, learning

Nicotinic
Bind nicotine
Linked to ion
channels

Muscarinic
Bind muscarine
Liked to 2nd
messenger system
through G protein

Fast and brief

response
Located at
neuromuscular
junctions,
autonomic
ganglia, and some
CNS

Slow and prolonged

response
Found on myocardial
muscle, certain
smooth muscle, in
some CNS regions

Cholinergi
c
Projection
Systems

Blumefeld,

Acetylcholine
Applying electrical stimulation to
pontomesencephalic region of the
brainstem elicits coordinated locomotor
movements.
Drugs that block the cholinergic
transmission in the brain causes delirium
and memory deficits.
Degeneration of cholinergic neurons in the
basal forebrain may be associated with
memory decline in Alzheimers disease

Myasthenia Gravis (MG)

ACh receptors on muscle membranes
are destroyed . Weakness becomes
more severe with repetitive use of a
muscle.
Rx: Anticholinesterase inhibits the
cholinesterase from breaking down
ACh.

Myasthenia Gravis (MG)

Reduced EMG amplitudes

over repetitive muscle
contractions.

Amines: Dopamine (DA)

Produced in substantia nigra of basal
ganglia and ventral tegmentum
Primarily an inhibitory effect in CNS
All DA receptors are 2nd messenger
systems to suppress the activity of
Ca++ channels.
Affects motor activity,
motivation/reward behavior, and
cognition

Dopamine Projecting
System

BG
Movement

Limbic
Reward
Addiction

Prefrontal
Working Memory
Attention

Neurologic Conditions
Associated with
Dopamine (DA)

Parkinsons Disease Case: DA in basal

ganglia
Depression/Cognitive: DA in forebrain
Drug addiction: cocaine and
amphetamines interfere with DA
reuptake into the presynaptic neurons,
allowing DA to activate receptors
repetitively
Schizophrenia: too much DA

Amines: Serotonin (5-HT)

Produced in raphe nuclei and GI tract
Serotonin regulates sleep-wake cycle,
cognition, perception of pain, breathing,
temperature, movements, and mood.
Serotonin is associated with depression,
anxiety, obsessive-compulsive disorder,
aggressive behavior, certain eating
disorders (release serotonin appetite)
Serotonergic neurons firing during sleep

Amines: Serotonin (5-HT)

Serotonin is happiness hormone.
Serotonin perception of pain. Low
levels of serotonin are associated with
depression.
Prozac (antidepressant) is a selective
inhibitor of serotonin reuptake (so
serotonin stays in the synaptic cleft
longer to bind with receptors)
SIDS may be associated with defected
serotonergic neurons.

Norepinephrine (NE)
Regulate functions of ANS, thalamus,
and hypothalamus
Modulate attention, sleep-wake cycle
Noradrenergic neurons firing in sleep
Attention-deficit disorders if often
treated with medications that enhance
NE transmission
level of NE is associated with vigilance,
alertness, and fight-or-flight response

Norepinephrine (NE)
Noradrenergic neurons involve in
sympathetic functions such as blood
pressure control
Similar to Serotonin, NE also
perception of pain in the CNS, and
plays a role in many psychiatric
syndrome
NE can cause depression
NE can cause anxiety (panic attack)

Serotonin
Projection
System

Noradrener
gic
Projecting
Systems

Blumefeld, 2010

Histamine
Found mainly in the hypothalamus.
Found mostly outside the nervous
system in mast cells that mediate
immune responses and allergic
reactions.
Role of histamine in the brain
Maintain the alert state
Excitatory effects on thalamus
Antihistamine medications can cause
drowsiness by blocking CNS histamine
receptors

Peptides: Substance P
Released from the terminals of some
sensory nerve fibers
Neurotransmitter function in the
nociceptive pathway
stimulates free nerve endings at the
site of injury and transmit pain
signals from the periphery to the CNS
Neuromodulator function in the chronic
pain syndrome
increase pain perception

Peripheral
sensitization
following cell
damage. Pain
signals cause the
free nerve endings
to release
substance P.
5-HT outside the
nervous system
stimulates the
nociceptive free
nerve
Hauser,endings.
2010
SP-substance P

Peptides: Endogenous
Opioids
(endorphin, enkephalin,
dynorphin)
Bodys natural pain

killers
Inhibit CNS neurons
involved in the
perception of pain
Exercise increases
endogenous opioids

Nitric Oxide (NO)

An free radical, highly reactive,
diffusible gas molecule with
neuromodulator effects
NO is important in the regulation of
cerebral blood flow, neurotransmission,
long-term potentiation, excitotoxicity
(i.e. neuronal death)
NO cause blood vessels to dilate
NO in excess is toxic to cells