Introduction to the

Pharmacology of
CNS Drugs
Dr. Selman Mohammed Selman
2024
ION CHANNELS & NEUROTRANSMITTER RECEPTORS

• The membranes of nerve cells contain two types

of channels defined on the basis of the
mechanisms controlling their gating (opening and
closing):
• voltage-gated
• ligand-gated channels.
1- Voltage-gated channels respond to changes
in the membrane potential of the cell, e.g. the
voltage-gated Na channel, Ca and K gated
channels.
• In nerve cells, these channels are responsible
for the fast action potential, which transmits the
signal from cell body to nerve terminal.
2- Ligand-gated channels ( ionotropic receptor)
are opened by binding of neurotransmitters to
the channels.
• Activation of these channels results in a brief (a
few milliseconds ) opening of the channel.

• e.g. nicotinic receptor, GABA receptor

3- G protein coupled receptor ( metabotropic
receptor) in which the binding of
neurotransmitter activates G protein which then
interacts with an ion channel.
These receptors subdivided into two types:
– The G protein interacts directly with the ion
channel, or
• The G protein activates an enzyme. The activated
enzyme generates a second messenger that
interact with ion channels. E.g. β adrenoceptor.
The synapes
• The communication between neurons in the CNS
occurs through synapses.
• The synaptic transmission
can be summarized as
follows:
• An action potential in the
presynaptic fiber
propagates into the
synaptic terminal and
activates voltage-sensitive
calcium channels in the
membrane of the
terminal.
• Calcium flows into the terminal, and the increase in
intraterminal calcium concentration promotes the
fusion of synaptic vesicles with the presynaptic
membrane.
• The neurotransmitter in the vesicles is released into
the synaptic cleft and bind the receptors on the
postsynaptic membrane.
• Binding of the neurotransmitter to its receptor causes
a brief change in membrane conductance
(permeability to ions) of the postsynaptic cell.
• The time delay from the arrival of the presynaptic
action potential to the onset of the postsynaptic
response is approximately 0.5 ms.
• The synapse functions like a valve, transmitting
information in one direction.
• But, some synapse can generate signals from the
postynaptic terminal to modify the release of transmitter.
• - - - - - - - - - - - are the best example of such retrograde
signaling. ???
• Postsynaptic activity leads to the synthesis and release of
- - - - - - - - - -, which then bind to receptors on the
presynaptic terminal.
• .
Synaptic potential
• In the CNS, receptors are coupled to
ion channels.
• Binding of the neurotransmitter to the
postsynaptic receptors results in a rapid
opening of ion channels.
• The results are producing either depolarization
or hyperpolarization of the postsynaptic
membrane, depending on the specific ions and
the direction
• of their movement.
A. Excitatory pathways
• Neurotransmitters can be classified as either
excitatory or inhibitory, depending on the nature
of the action they elicit.
• Stimulation of excitatory neurons causes a
depolarization of the postsynaptic
membrane.
• These excitatory postsynaptic potentials (EPSP)
are generated by the following:
1) Stimulation of an excitatory neuron causes
the release of neurotransmitters, which bind
to receptors on the postsynaptic cell
membrane. This causes a increase in the
permeability of sodium (Na+) ions.
1) The influx of Na+ causes a weak
depolarization, or EPSP, that moves
‫ابجتاهااا‬
the postsynaptic potential toward its
firing threshold.
‫لك ما تتحفز ينورن ارثك لك ما‬
‫وندل وناقل صعيبة ارثك وشغل‬
‫احسن‬
2) If the number of stimulated
excitatory neurons increases, more
excitatory neurotransmitter is
released. This ultimately causes
the EPSP depolarization of the
postsynaptic cell to pass a
threshold, thereby generating an
all-or-none action potential.
 EPSP IPSP
depolarization of the postsynaptic hyperpolarization. of the
membrane. postsynaptic membrane.

Stimulation. of. an excitatory Stimulation of inhibitory

neuron neurons

increase in the permeability of increase in the

(Na+) permeability of specific
ions, such as K+ and Cl−.

potential toward its firing threshold. potential away from its

firing. threshold.
• B. Inhibitory pathways
• Stimulation of inhibitory neurons causes
hyperpolarization of the postsynaptic
membrane.
• These inhibitory postsynaptic potentials
(IPSP) are generated by the following:

1) Stimulation of inhibitory neurons releases

neurotransmitters, such as GABA or glycine,
which bind to receptors on the postsynaptic
cell membrane. This causes a increase in the
permeability of specific ions, such as K+ and
Cl−.
2) The influx of Cl− and efflux of K+ cause an
hyperpolarization, or IPSP, that moves
the postsynaptic potential away ‫عهنا‬from
‫عبيد‬
its
firing threshold.
• This diminishes the generation of
action potentials.
Sites of Drug Action
All of the drugs that act in the CNS produce their effects by
modifying some step in chemical synaptic transmission.
Following figure illustrates some of the steps that can
be altered.
steps at which drugs can alter synaptic transmission:
Anti-epeliptic. drug
(1) Action potential, e.g. Carbamazepine reduces the
propagation of abnormal impulses in the brain by
blocking sodium channels, thereby inhibiting the
generation of repetitive action potentials in
epeliptic focus
(2) synthesis of transmitter, e.g. p-
chlorophenylalanine blocks the synthesis of
serotonin
Antagonist
(3) storage; e.g. reserpine depletes the synapses
of monoamines by interfering with intracellular
storage
(4) metabolism; e.g. selegiline inhibits monoamine
oxidase B which metabolizes dopamine.
CNSstimulators
(5) release ;e.g. amphetamine induces the
release of catecholamines from adrenergic
synapses.
 addictive stimulant. drug
(6) reuptake; e.g. cocaine blocks the uptake of
catecholamines at adrenergic synapses
(7) degradation; e.g. Anticholinesterases block
the degradation of acetylcholine
(8) receptor : e.g. agonists or antagonists.
(9) receptor-induced increase or decrease in ionic
conductance: barbiturates can block the channel
of many excitatory ionotropic receptors
CENTRAL NEUROTRANSMITTERS
 ‫مُأمل‬
Acetylcholine MAML

Functions:
1- Motor control
2- Learning and memory
3- Alertness
Acetylcholine receptors:
Types of Mechanisms
receptors
Excitatory: :↓ K+ conductance
M1 ,↑IP3, DAG

Inhibitory: ↑ K+ conductance, ↓
M2 cAMP

Excitatory: ↑ cation conductance

Nicotinic
 MAP 🗺
Norepinephrine Mood Arousal Pressure
Functions:
1- Mood (depression or mania)
2- Blood pressure regulation
3- Arousal (alertness and explority activity)
Norepinephrine Receptors:
Types of Mechanisms
receptors

Excitatory: :↓ K+ conductance , ↑IP3,

α1 DAG M1 ‫فنس‬
4+2 ‫وسمتقبالت اسلريووتنني‬
Inhibitory( presynaptic)
α2 ↓ Ca+2 condoctance
↑K+ conductance
↓ cAMP
Excitatory:
ß1 ↓K+ conductance
↑ cAMP

Inhibitory: ↑ Adenylyl cyclase and

ß2 ↑cAMP
Serotonin
Functions:
1- Hallucinations and behavioral changes
2- Mood
3- Sleep, and wakefulness
4- Feeding and appetite
 Serotonin receptors
‫سمتقبالت‬٦ ‫حلد اآلن مكشتفني‬
Types of Mechanisms
receptors

Inhibitory:
5-HT1A ↑K+ conductance
↓ cAMP
5-HT2A Excitatory:↓ K+ conductance, ↑IP3, DAG

5-HT3 Excitatory: ↑ cation conductance

5-HT4 Excitatory:↓ K+ conductance, ↑IP3, DAG

Dopamine
Functions:
1- Motor effect
2- Behavioral effects
3- Tuberohypopheyseal system •
 Dopamine
Functions Distribution in the Types of Mechanisms
brain receptors

Motor effect Nigrostriatal ↑ adenylyl cyclase D1, D5

system ↑ cAMP

Behavioral effects Mesolimbic and Inhibitory: D2, D3, D4

mesocortical ↓adenylyl cyclase
system

Endocrine control Tuberohypopheyseal

( decrease prolactin system
secretion)
Amino Acids
• The amino acids in the CNS fall into two
categories:
• the acidic amino acid glutamate
• and the neutral amino acids glycine and
GABA.
• They are present in high concentrations in the
CNS and are extremely potent modifiers of
neuronal excitability.
A. 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 Ca
2+ -dependent exocytosis.
• Glutamate acts on postsynaptic glutamate
receptors and is cleared by glutamate transporters
present on surrounding glia.
• Glutamate is converted to glutamine by glutamine
synthetase, taken up by the nerve terminal, and
converted back to glutamate by the enzyme
glutaminase.

Glutamimine synthetase
Glutamate Glutamine
• Glutamate mediates its actions through :three
receptor :
• and N -methyl-D-aspartate (NMDA).
• α-amino-3-hydroxy-5-methylisoxazole-4-
propionic acid (AMPA),
• kainic acid (KA),
•
• .
B. GABA and Glycine
• Both GABA and glycine are inhibitory
neurotransmitters.
• Glycine present in:
• the spinal cord
• brainstem.
• GABA present throughout the CNS, including the
spinal cord.
• It is interesting that some interneurons in the
spinal cord can release both GABA and glycine.
• Glycine receptors are pentameric structures that
are selectively permeable to Cl – .
• Strychnine, which is a potent spinal cord
convulsant and has been used in some rat poisons,
selectively blocks glycine receptors.
• GABA receptors are divided into two main types:
• GABA A : fast component
• and GABA B : slow component
• GABA A receptors are ionotropic receptors and,
like glycine receptors, are pentameric structures
that are selectively permeable to Cl – .
• These receptors are selectively inhibited by
picrotoxin and bicuculline, both of which cause
generalized convulsions.
• GABA B receptors are metabotropic receptors that
are selectively activated by the antispastic drug
baclofen.
 Glycine
Functions Distribution Types of Mechanisms
in the brain receptors
Inhibitory effects Grey matter of Glycine receptor Inhibitory:↑ Cl -
spinal cord conductance
 Adenosine
Functions Types of Mechanisms
receptors
Inhibitory: A1 G-protein
drwsiness, coupled receptor
anelgesia, A2A (GPCR)
reducing anxiety,
anticonvalsant,
neuroprotuction A2B

A3
 ‫كذالك ادح انلواقل الصعيبة عتترب‬ ATP
Functions Types of Mechanisms
receptors

Nociception‫تمحسسه أللمل‬ P2X GPCR

(released by
tissue damage
causes pain)
P2Y Ligand –gated
ion channel