INTRODUCTION TO
NEUROCHEMISTRY
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Neural transmission
Is a biochemical process, carried out by
neurotransmitter and neuromodulator
substances
↓ They diffuse across the synaptic clefts that
separate individual neurons
↓ This permits one neuron to be able to
communicate with the next neuron
↓ Allow for communications among diverse
regions of the nervous system
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The propagation of action potential will
cause neurochemical transmission
especially through ligand-gated channels
Neurotransmitters are synthesized by
enzymes within the presynaptic axon
terminals and stored in presynaptic
axon vesicles
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• Other neurotransmitters, such as
acetylcholine, are synthesized
elsewhere in the cell and subsequently
transported into their vesicle for
transmission
• A given presynaptic terminal may
synthesize, store, and release
multiple neurotransmitters
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Events at presynaptic axon terminal
When the action potential of the neuron
reaches the presynaptic terminal
An influx of calcium (Ca2+) ions into the
terminal (depolarizing it)
Vesicles are transported to presynaptic
membrane & discharge their contents
(i.e., neurochemical transmitters) into
the synaptic cleft
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arrival of the action potential at the terminal bouton - a
release of calcium Ca2+ into the terminal bouton - the vesicle
migrate to the surface of the bouton, - vesicles release
its contents into the synaptic cleft.
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Either too much or too little release
of a neurotransmitter at the synapse
may be associated with behavioral
dysfunction
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Neurotransmitter Receptors
Receptors - specially designed proteins
manufactured within the endoplasmic
reticulum and Golgi apparatus of the
neuron
Each neurotransmitter has its own
unique set of receptors into which it fits
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Each neurotransmitter generally has
multiple receptor subtypes
just as a master key may open several
different locks
Various receptor subtypes may be found
at a single synapse
Different receptor subtypes may
predominate at different anatomical sites
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• Neurotransmitters act by binding to a
particular receptor after they released &
initiates a secondary response
• Different receptors subtypes, even though
stimulated by the same neurotransmitter,
may result in a very different behavioral
response
• Drugs acting on same receptor but at
different sites result in different effect
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Receptors subtypes
1. G-protein-linked receptors
Known as metabotropic
do not have a direct impact on ion channels
& produce their effects via different
mechanisms
Receptors for slow acting such as DA, NE, 5-
HT
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Binding of the neurotransmitter (first
messenger) to the receptor
conformational change in the receptor
binding to G-protein inside the cell
Membrane activation of
intracellular enzyme Produces
change in the cell (second
messenger)
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This second-messenger effect can be:-
1. Activating other enzymes in the cell
2. Impacting on the DNA of the cell,
which in turn causes the synthesis or
degradation of other enzymes or
proteins
3. Modulation or opening of ion channels
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2. Ligand-gated receptors
Known as ionotropic receptors
Exert their effects through ion channels
When stimulated by an agonist or
neurotransmitter, they increase the flow of
ions through the channel
They are the receptors for fast-acting
neurotransmitters such as glutamate and
GABA
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Allosteric Modulation
Each synapse may have receptors that
are responsive to more than one type of
neurotransmitter.
Single receptors may have multiple
binding sites that are responsive to
different chemical molecules
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In multiple binding sites, one
neurotransmitter will be primary and the
other neurotransmitter will act as
secondary neurotransmitter
These secondary neurotransmitters
(modulators) are unable to effect a
response independent of the primary
neurotransmitter
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• They can alter the response of the
receptor once the primary
neurotransmitter adheres to its
binding site which is known as
allosteric modulation
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a)primary neurotransmitter produces a response-opening
of an ion channel b) Binding by the secondary
neurotransmitter itself has no impact, c) combined with
primary neurotransmitter, the effect of the latter is 19
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Allosteric modulation may be either
positive or negative
If positive - enhance or augment the
effect produced by the primary
neurochemical transmitter
Negative - reduce or possibly even
reverse the normal response elicited
by the primary neurotransmitter
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Autoreceptors
Not all receptors are located on the
postsynaptic membrane
Receptors sensitive to the released
transmitter commonly are found either on
the dendrites (or cell body itself) or at the
same presynaptic terminal from which the
neurotransmitter was released.
They may serve as feedback receptors for
neurochemical transmitters within a
particular cell which known as
autoreceptors
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Autoreceptors - In the absence of autoreceptor stimulation,
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With stimulation of the somatodendritic autoreceptors
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Heteroreceptors
A neurotransmitter not only may affect its
own release via autoreceptors
Some diffuse to their own receptors
located on other neurotransmitter’s
neurons, where it either inhibit or facilitate
release of a second neurotransmitter
found on that neuron which known as
heteroreceptors
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Receptor Regulation
Regulation of the synthesis of
receptors can be:-
Up-regulation of receptors - When
there is relative deficiency of a
particular neurotransmitter at a given
synapse, the cell produce more
receptors
Down-regulation of receptors - If
there is too much neurotransmitter, the
cell reduce the number of its receptors
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Neurotransmitter removal
A neurotransmitter needs to be cleared from the
synapse, once it carry out its intended activity to:-
Prevents the possibility of tonic stimulation of
the postsynaptic membrane or presynaptic
autoreceptors
Prepares the synapse for the next stimulus
generated by the presynaptic neuron
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This happened through three basic ways:
Neurotransmitter might be degraded by
enzymatic action in the synaptic cleft
It may transported back (Re-uptake) into
the presynaptic terminal again to stored
until needed
Simply diffuse away from the synaptic cleft
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Degradation
Different enzymes are involved in the
breakdown of different neurotransmitters
Catechol-0-methyltransferase (COMT) -
degradation of NE and DA.
Acetylcholinesterase (AChE) - acetylcholine
down into choline and acetate
Monoamine oxidase (MAO) -destruction of
NE, DA, and 5-HT
Gamma-aminobutyric acid transaminase
(GABA-T) - break down of GABA
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Reuptake
To terminate the activity of a
neurotransmitter in the synaptic
cleft, they taken back to from which
they released
Accomplished by specialized chain of
proteins known as transport pumps
or reuptake proteins, or transport
carriers
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Diffusion
Glutamate is diffused back into
either the presynaptic terminal
or the neighboring glial cells
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Drug Actions
Drug interact with neurotransmitters
through 3 major mechanisms
Drug–Receptor Interactions
Influencing the enzymatic Actions
Reuptake inhibition
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a. Drug–Receptor Interactions
Many drugs, various toxic agents, and
other psychoactive substances can
bind to receptor sites
Then produce their effects through
their capacity to occupy specific
receptors
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The most commonly known effects are:-
Agonists- any substance that activate
the receptor.
Antagonists- simply blocks the
receptor site, preventing an agonist (or
other substance) from binding at that
site
Partial Agonists - either as a partial
agonist or as a partial inverse agonist
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A) at rest, B) stimulation by an agonist, C) by a partial agonist, D) by
an antagonist
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b. Enzymatic Actions
Antagonist drugs also may block the
actions of enzymes
Different drugs might act as either
reversible or nonreversible inhibitors
of enzymes that degrade the
neurotransmitters
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c. Reuptake inhibition
Inhibits the reuptake of a
neurotransmitter from the synaptic
cleft back into the presynaptic
terminal Increased amount of the
neurotransmitter in the synaptic
space Therapeutic effect
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Drug Side Effects and Receptors
The drug interacts with receptors at
presynaptic, synaptic cleft & postsynaptic
areas of the neuron
Side effects generally result when a given
medication either acts on:-
1. Receptors other than the one(s)
primarily targeted
2. Receptors of the targeted transmitter
that may be present in organs or
functional systems other than the
one(s) intended
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• Thanks
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