Chapter 21 : Introduction to the Pharmacology of
CNS Drugs
PRINCIPLES
1. Acts on a specific receptor (Cholinergic
receptors, Histaminergic receptors,
GABAergic receptors)
2. Leads to better understanding of the
CNS physiology (mood, learning,
memory, sleep-wake cycle)
3. Better understanding of CNS disease
pathophysiology ( Parkinsons, Multiple
sclerosis, Insomnia )
ORGANIZATION OF THE CNS
- Composed of the brain and spinal cord
- Integrates sensory information
- Generates motor output and behaviors
I. Neurons
Electrically excitable cells
Transmit information via
electrochemical process
Classified by function, location and
neurotransmitter released
Basic Anatomy
A. Soma Cell body
B. Axon Carries out the signal
of a neuron from the cell body
C. Dendrites- Receives
information from other neurons
and conducts it to the cell body
Synapses
o Specialized junctions where
axon terminals make contact to
other neurons
o Where neurotransmitters are
released
II. Neuroglia
Non-neuronal support cells
Types :
o Astrocytes
Homeostatic support
Recycling and removal
of neurotransmitter
Its Pedicle wraps
around blood vessels that form
the BBB
o Oligodendrocytes
Forms the myelin
sheath in the CNS
Cannot regenerate
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Preserves action
potential in CNS
o Schwann cell - Forms the
myelin sheath in the PNS
o Microglia- Macrophages in
CNS
III. Blood-Brain Barrier (BBB)
Impedes the entry of some substances to
our brain
The pedicle of the astrocyte
Hydrophobic barrier ( non-polar
substances can easily pass the BBB )
Polar substances require a specific
carrier molecule to pass through the
BBB ( carrier mediated transport )
ION CHANNEL & NEUROTRANSMITTER
RECEPTORS
Ion channels
I. Voltage gated
Responds to membrane potential
Abundant in the Axon Hillock
Responsible for the FAST action
potential
Includes the Na Channels
Other voltage gated channels are located
in the soma and dendrites
Abundant in Ca and K channels
II. Ligand gated ( Ionotropic receptors)
Requires a neurotransmitter / chemical
substance to open the channel
Fast synaptic transmission
Channel opens briefly
III. Metabotropic receptors
7 transmitter G protein-coupled
receptors ( serpentine )
Also requires a neurotransmitter for G
protein coupling
Found in soma, pre and post synaptic
membranes
Membrane delimited pathway
o Interactions wherein the G
protein coupled metabotropic
receptors can :
Act on diffusible
secondary messengers
(cAMP,DAG,IP3)
that modulates the
 voltage gated channels
or other ion channels
nearby through a kinase
phosphorylating the ion
channel for them to
open up
Cause production of ion
channels (speeds up the
influx and efflux)
o Acts on Ca and K channels
G protein + Ca
channel= inhibition of
channel function
(leads to inhibition of
neurotransmitter release in the
presynaptic terminal )
G protein + K channel=
activation of channel
function
(leads to the opening of K
channels in the postsynaptic
terminal)
SLOW synaptic postsynaptic inhibition /
transmission
THE SYNAPSE AND SYNAPTIC POTENTIAL
The effects are produced by the ion
current in the synapse
Calcium channels in the presynaptic
terminal are responsible for the release
of the neurotransmitters to the synaptic
cleft as it binds to its receptor in the
postsynaptic terminal and opens the
channels. ( Remember and refer to the
synapse in p. 203 fig 8.12 of Seeleys)
Summation- addition of excitatory
postsynaptic potential ; incremental
o Temporal summation
summation from a single neuron
wherein each signal is separated
by time
o Spatial summation - summation
from 2 or more separate neurons
wherein
Post synaptic potentials
o Excitatory postsynaptic
potential (EPSP)
Depolarizing
Opening an Na or Ca
channel
Na carries positive
charge that increases the
resting membrane to the
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more positive spectrum
bringing it closer to the
threshold potential and
eventually breaching it
(spatial summation) for
the neuron to produce
action potential
( remember and refer to
Figure 8.7 , 8.8 and 8.9
pp. 199-201 of
Seeleys)
Temporal summation
causes another action
potential ( refer to
Figure 21-3 p 359 of
Katzungs)
Same with Ca
Closes the K (intracellular)
channel
Retain positive charge
inside the cell
o Inhibitory postsynaptic potential
(IPSP)
Hyperpolarizing
Opens K (intracellular)
or Cl (extracellular)
channel
Opening K channel will
result to K moving out
faster thus making the
intracellular membrane
more negative/ less
positive
Opening Cl channel will
bring in negative charge
inside the cell thus
making the intracellular
membrane more
negative
Action potentials fails
when there is IPSP even
if it is evoked by an
excitatory postsynaptic
potential under resting
membrane potential
(RMP)
o Presynaptic inhibitory effects
can also be produced by
decreasing the Ca conductance
resulting to the inhibition of the
fusion of the presynaptic vesicle
and the presynaptic membrane
thus preventing the release of
 the neurotransmitter ( inhibits 3. Storage (membrane bound preformed
transmission of the action vesicles)
potential) 4. Metabolism
5. Release (especially Ca channel inhibitors)
SITES OF DRUG ACTION 6. Uptake ( either back to the nerve ending or it
goes to the glial cells for recycling)
Most CNS drugs act directly on synapses 7. Degradation
Can activate or block pre and post synaptic receptors 8. Receptor for the transmitter
for specific transmitters 9. Receptor induced increase or decrease in
These drugs may interfere with the action of ionic conductance
secondary messengers ( These drugs target 10. Retrograde signaling
metabotropic receptors) o The post synaptic neuron signals the
Some drugs act upon directly on the molecular presynaptic that the neurotransmitter
components of ion channels on axons in the receptor is already in excess
If ion channels are inhibited = no conductance = no resulting to the liberation of a
action potential diffusible messenger from the
~ Ex.1 Carbamazepine and Phenytoin stabilizes the postsynaptic terminal that travels
membrane potential thus preventing seizure across the synaptic cleft and
~ Ex.2 General Anesthesia blocks the entry of ions activates the receptors in the
in ion channels therefore there is no action potential presynaptic terminal resulting to the
and sensation cannot be felt on the site of alteration(decrease) in synaptic
application. transmitter release so as to avoid
* (Examples 1 and 2 exert their effect through direct resistance
interactions with the molecular components of the
ion channel on axons) CELLULAR ORGANIZATION OF THE BRAIN
~ Ex.3 Parachlorophenylalanine inhibits serotonin I. Hierarchical systems
synthesis
Include all the pathways involved in SENSORY
~ Ex.4 Reserpine inhibits storage of
PERCEPTION and MOTOR CONTROL
catecholamines/monoamines ( stabilizes vesicles of
cathecolamines ) Motor Neurons
~ Ex.5 Amphetamine induces release of 1. Upper
cathecolamines ( p. 360 and chapters 6,9,&32 ) o Pre central gyrus
~ Ex.6 Capsaicin causes the release of substance P 2. Lower
from sensory neurons o Ventral horn
~ Ex.7 Tetanus toxin blocks the release of Sensory Neurons
transmitters 1. Upper
~ Ex.8 Anticholinesterase blocks the degradation of o Post central gyrus
Cathecolamines (Ach) 2. Lower
o Dorsal root ganglion --- Dorsal horn
CNS drugs also act on synthesis, storage, release, Pathways are/have :
metabolism and reuptake of neurotransmitters such o Traced/ delineated
as SSRI or selective-serotonin reuptake inhibitors o Large MYELINATED fibers
Selectivity of CNS drug action o Occurs in bursts of action potential
1. In most cases, different neurotransmitters Hierarchical pathway neuron types
are released by different groups of neurons 1. Relay or Projection Neurons
Segregated into neuronal o Large soma
systems that correspond to o Long distance transmission
different CNS functions o Synapses to local inter-neurons
2. There is a multiplicity of response for each o Excitatory
neurotransmitter
o Involves ionotropic receptors (short
Steps wherein which drugs can alter synaptic
duration)
transmission ( refer to p 360 ; figure 21-4 of o Releases glutamate and aspartate
Katzungs )
2. Local Circuit Neurons
1. Action potential in presynaptic fiber
o Smaller soma
2. Synthesis of transmitter
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 o Axons spread in a tree like manner
(arborize) in the immediate vicinity of a
cell body
o Inhibitory
o Releases GABA and glycine
(interneurons)
Types of hierarchical pathways ( refer to figure
21-5 p. 361 of Katzungs)
1. Feed-forward and Feed-back (recurrent)
pathways
o Feed-forward pathways
One direction
From input to output
One neuron at a time
o Feed-back pathways
The output of the neuron is
added to the next input and fed
back to the same neuron
Can receive a sequence of
values as input and release a
sequence of values as output
2. Axoaxonic interaction
o Axon of an inhibitory neuron acts upon
the presynaptic axon terminal fiber thus
inhibiting the release of
neurotransmitters
o Found in terminals of sensory axons
o Presynaptic inhibition
II. Nonspecific or diffused neuronal systems
o Contains neurotransmitters like Ach and
monoamines
o Varicosities ; broadly distributed
o Differs from hierarchical system
o Cell bodies with small nuclei in the
brainstem produce neurotransmitters of
this system ( Ex. Raphe nuclei : 5-HT,
serotonin )
o Neurons diffuse throughout the brain
and spinal cord
o Unmyelinated = slow conduction
o Innervates several functionally different
parts of the CNS
o Synapses to modulating neurons within
the hierarchical system
o Neuronal systems in the neocortex
Have tangential(diverging)
organization = influences large
areas in the cortex
o Most neurotransmitters that are under
the neuronal systems act predominantly
on metabotropic receptors
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o Ex. Norepinephrine : Locus caeruleus *
( in the caudal pontine)
o Long lasting synaptic effects
o Conveys information on vast areas of
the CNS as it must be affected
simultaneously and uniformly
o SLEEP,WAKING,ATTENTION,
APPETITE, EMOTIONS
CENTRAL NEUROTRANSMITTERS
Criteria for transmitter identification
1. Localization: A suspected transmitter must
be located in the PRESYNAPTIC terminal
of interest
2. A suspected neurotransmitter must be
released from the presynaptic terminal in
response to neuronal activity and increase in
presynaptic Ca concentration/conductance
3. Application of a candidate substance should
produce a response that mimics the action of
the actual neurotransmitter released
4. Application of a selective antagonist should
block the response of applying a candidate
substance
~ There should be predictability ( 3 &4 )
o To produce the same sort of
postsynaptic response that is seen with
physiologic activation of the synapse
(ie, must exhibit synaptic mimicry)
Amino Acid Neurotransmitters
1. Glutamate
o Excitatory
o For learning and memory ( NMDA )
o Released by Ca dependent exocytosis
o Cleared by glutamate transporters found
in the glial cells
o In the glia
Glutamate ---------> Glutamine
via glutamine synthetase
o When taken back to the presynaptic
terminal
Glutamine ---------> Glutamate
via enzyme glutaminase
o Vesicular glutamate transporter
(VGLUT)
Achieves high concentration of
glutamate in synaptic vesicles
o Ionotropic glutamate receptors
i. AMPA
a. Heterotetramers
 b. GluA1-GluA4 e. Requires the
c. Permeable to binding of both
Na and K Glycine and
Glutamate
( contain GluA2 f. NMDA pore is
subunits) usually blocked
d. Only permeable by Mg
to Ca when g. Mg is removed
lacking GluA2 by strong
subunits depolarization
(present on thus opening
inhibitory inter- the NMDA
neurons) channel
e. Uniformly h. For the NMDA
distributed receptor
f. Receptor channel to
activation open: 1.
results in Glutamate must
channel bind to the
opening at receptor
RMP 2. Membrane
ii. KA should be
a. GluK1-GluK5 depolarized
b. GluK4 and i. Increase in
GluK5 are Intracellular
unable to form Ca
their own concentration
channels + channel
c. Usually opening =
permeable to Long-term
Na and K potentiation
d. Receptor (LTP) or
activation increase in
results in synaptic
strength
channel
opening at o Metabotropic glutamate receptors
RMP G protein coupled
Act indirectly on ion
iii. NMDA
a. Widely channels
distributed mGluR1-mGluR8
along the CNS Divided to 3 groups
b. Highly i. Group 1
permeable to Postsynapti
Ca , K, Na -cally
c. NMDA located
receptors Decreases
require GluN1 K
subunits
d. May contain 1 conductanc-
or 2 GluN2 e
subunits Activate
( GluN2A- PLC which
GluN2D) leads to IP3

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 mediated Increase Cl
Ca release (extracellular)condu
Excitatory -ctance
ii. Groups 2 and 3 Fast component
Presynaptic Ionotropic receptors
ally located Pentameric
Inhibitory
receptors
Activation
causes Ca
GABAb
channel
Presynaptically
inhibition
inhibit Ca
and
conductance
transmitter
Postsynaptically
release
induce K
inhibition
conductance
Only
Metabotropic
activated
receptors
when Slow component
glutamate Long lasting
concentrati Inhibit adenyl
on is too cyclase thus
high decreasing cAMP
Activation
generation
of these
receptors ACETYLCHOLINE (ACH)
inhibits
adenyl CNS responses are mediated by large G protein
cyclase and coupled muscarinic receptors for the muscarinic
decreases type
cAMP Cholenergic receptors
generation o M1 receptors
2. GABA and Glycine 1. Slow excitation
o Inhibitory 2. Produced by decreasing
o GABA is the primary membrane permeability to K
neurotransmitter in mediating IPSP 3. Activate PLC which leads to
o Released from local interneurons IP3 mediated Ca release
o GABA releasing neurons 4. More widespread muscarinic
All over CNS ( inc spinal action
o M2 receptors
cord)
o Glycine releasing neurons 1. Slow inhibition
2. Opens K channels
Abundant in the spinal cord
3. Inhibit adenyl cyclase thus
and brain stem
decreasing cAMP generation
o Glycine receptors
Cognitive functions
Pentameric
Renshaw cells ( Postsynaptic parasympathetic
B- alanine
Selectively permeable to Cl neurons)
o Nicotinic ; ionotropic = ( cation
Blocked by strychnine
o GABA receptors conductance)
GABAa Characterized with diffuse projections

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 Include neurons in Neostriatum, Medial septal Found on locus
nucleus and reticular formation caeruleus area
Pathway Presynaptic
1. Ch5-Ch8 ( cholinergic -Decreases Ca
brainstem nuclei) conductance
2. Medial septal nucleus (MSN) , Postsynapic-
Diagonal band of Broca (DB), Increases K
Nucleus Basalis of Meynert permeability
and decreases
MONOAMINE NEUROTRANSMITTERS cAMP
1. Dopamine B1
o Pathway Excitatory
Substantia Nigra--- Decrease K
Neostriatum conductance
Ventral Tegmental Area Increases
(VTA) ---nucleus cAMP
accumbens---limbic formation
cortex B2
o Regulates pituitary functions Inhibitory
o Metabotropic receptors Increase in
D1 like ( D1 and D5)
cAMP
D2 like ( D2,3,4) Increase in
o Slow inhibitory
electrogenic Na
o G protein Coupled
pump
o D1 receptor activation
o Most regions Norepinephrine
Increase cAMP
enhances excitatory inputs
formation
Direct
o D2 receptor activation
Blockade of K
( same as GABAb)
Presynaptic conductance
Decreases Ca Indirect mechanisms
Involves
conductance
Postsynaptic inhibition of
Increases K inhibitory local
conductance circuit neurons
Decreases o Attention and arousal
cAMP
3. Serotonin (5-HT)
formation o Pathway originates from
2. Norepinephrine
Raphe nuclei
o Pathway
o Contained by unmyelinated
Locus caeruleus/lateral
fibers
tegmental area
o Metabotropic except for 5-HT3
o Metabotropic receptors
A1 (ionotropic)
o 5-HT3 exerts rapid excitatory
Excitatory
Decrease K action
Increase o On most sites 5-HT exerts
DAG,IP3 inhibitory actions
o Regulation of all brain functions
A2 ( hyperpolarization)
Inhibitory

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 o 5-HT1a o Substance-P = slow excitatory role
Inhibitory o Transfer noxious stimuli
Increase K conductance o Tachykinins
Decrease cAMP o Excitatory : decrease K conductance ; increase
formation DAG ,IP3
o 5-HT2a
Excitatory OPOIDS
Increase IP3,DAG
Decrease K o Inhibitory
o Metabotropic
conductance
o Inhibits adenyl cyclase- decrease in cAMP
o 5-HT3
Excitatory formation
Increase cation o Mu = Endorphin= Presynaptic
o Delta= Enkephalin=Postsynaptic
conductance
o Kappa = Dynorphin =Postsynaptic
o 5-HT4
Excitatory OREXIN
Decrease K
conductance o Peptide neurotransmitters
4. Histamine o Also known as Hypocretins
o Made by Tuberomammillary o Released from large, dense core vesicles
nucleus (TMN) located in the o Metabotropic
ventral posterior hypothalamus o OX1- Excitatory
o Throughout the CNS o OX2- Excitatory
o Arousal , attention, feeding o Co-releases glutamate
behavior, memory o Associated with wakefulness, energy
o H1-H4 homeostasis, reward
o Metabotropic receptors o Activate monoamine and Ach molecules
H1
Excitatory ENDOCANNABINOIDS
Decrease K
o Primary psychoactive ingredient in cannabis
conductance
Increase DAG o Retrograde synaptic messengers ( released from
and IP3 postsynaptic terminal and travels back to the
H2 presynaptic terminal, activating CB1 receptors
Excitatory to suppress the release of the neurotransmitter)
Decrease K o Activates widely distributed cannabinoid
conductance receptor
Increase cAMP CB1
formation Primarily located on presynaptic
H3 terminals
Inhibitory Inhibitory- presynaptic = Ca
autoreceptors conductance decreases; cAMP
production decreases
NEUROPEPTIDES Ligands include
Anandamide
o Found in the periphery 2-AG
o Act as neurotransmitters o Rapidly
o Packaged in large dense core vesicles synthesized
o Release is independently regulated o Response to
o Most are metabotropic
depolarization
o Serve modulator roles
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NITRIC OXIDE
o Nitric oxide synthase ( NOS ) is activated by
calcium-calmodulin
o Nitric oxide is generated by the activation of
NMDA which increases the conductance of Ca
o Retrograde messenger
o Known for long term depression of synaptic
transmission in the cerebellum
o Released by the endothelium as a vasodilator
PURINES
o Receptors include
Adenosine
Acts on metabotropic adenosine
1 /A1 receptors
Presynaptic A1 receptors
inhibit calcium channels thus
inhibit the release of
neurotransmitters
ATP
Released from catecholinergic
synaptic vesicles
Converted to adenosine
extracellularly by nucleotidases
P2X family
Nonselective ligand-
gated cation channels
Ionotropic
P2Y family
Metabotropic
UTP
UDP
o Play a role in neuropsychiatric disorders
o Memory, wakefulness and appetite
PATTERNS AND TRENDS
**Refer to Table 21-2 p.364-365 for a more
complete summary
1) cAMP and K are indirectly proportional
2) (IP3, DAG) and K are indirectly
proportional
3) Ca and cAMP are directly proportional
4) IP3 and DAG are requirements to
produce Ca hence (IP3,DAG) and Ca
are directly proportional
5) Ca : Presynaptic
6) K : Postsynaptic
7) IP3 and DAG never decreases
8) cAMP production only increases when
excitatory
9) K and cAMP lagi magkasama sa
inhibitory
10) K and IP3,DAG lagi magkasama sa
excitatory
11) 5-HT1A receptors and GABAb
receptors share the same K channel.
12) Decrease in K : increase in IP3,DAG
~Ach M1= 5-HT2a= Norepinephrine
A1= Histamine H1=Tachykinins
NK1,2,3
13) Increase in K: decrease in cAMP
~Ach M2 = 5-HT1a = Opoids
kappa=Opoids delta
14) Inhibitory post and presynaptic
~Dopamine D2=GABAb=
Norepinephrine A2
15) Excitatory increase in cation
conductance
~Ach Nicotinic=
NMDA(Ca)=AMPA=KA=5-HT3
16) Inhibitory Cl conductance
~ GABAa= Glycine B-alanine
17) Decrease in Ca : Decrease in cAMP
~ Glutamate metabotropic(excitatory
post synaptic) = Opoid Mu =
Endocannabinoids CB1
18) Decrease in K : Increase cAMP
~ Norepinephrine B1= Histamine H2
19) Special
a. DOPAMINE- D1:increase
cAMP: inhibitory
b. SEROTONIN- 5-HT4: decrease
K conductance: excitatory
c. HISTAMINE- H3=Inhibitory
auto receptors
d. OREXINS-
OX1:OX2:Glutamate co
release: excitatory
e. NOREPINEPHRINE increase
in sodium pump ; increase Ca

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