CNS Pharmacology

Drugs acting in the central nervous system

(CNS) were among the first to be discovered by
primitive humans and are still the most widely
used group of pharmacologic agents.
In addition to their use in therapy, many drugs
acting on the CNS are used without
prescription to increase the sense of well-being
• The mechanisms by which various drugs act in
the CNS have not always been clearly
understood. In recent decades, however, dramatic
advances have been made in the methodology of
CNS pharmacology. It is now possible to study the
action of a drug on individual cells and even single
ion channels within synapses. The information
obtained from such studies is the basis for
several major developments in studies of the CNS.
Nearly all drugs with CNS effects act on specific
receptors that modulate synaptic
transmission. A very few agents such as
general anesthetics and alcohol may have
non-specific actions on membranes
(although these exceptions are not fully
accepted), but even these non-receptor-
mediated actions result in demonstrable
alterations in synaptic transmission.
 Neurotransmission in the CNS
• In many ways, the basic functioning of neurons
in the CNS is similar to that of autonomic nerve
system (ANS). For example transmission of
information in both CNS and periphery involves
release of neurotransmitter that diffuse across
the synaptic space to bind to specific receptors
on the post-synaptic neurons/membranes, the
recognition of neurotransmitter by the
membrane receptor of the post-synaptic
neurons triggers intracellular changes.
• However, several differences exist between neurons in
peripheral ANS and those in CNS.
• The circuitry of CNS is much more complex than that
of ANS, and number of synapses in the CNS is far
greater. The CNS unlike peripheral ANS contains
powerful networks of inhibitory neurons that are
constantly active in modulating the rate of neuronal
transmission,
• In addition, the CNS communicates through use of
multiple neurotransmitters where as ANS uses only
two primary neurotransmitters, Acetylcholine and Nor-
epinephrine.
 Synaptic potentials(SP)

• In the CNS, receptors at most synapses are coupled

to ion channels. Binding of the neurotransmitter to
post-synaptic membrane receptors results rapid
but transient opening of ion channels. Open
channels allow specific ions inside and outside
membrane to follow down their concentration
gradient. The resulting change in the ion
composition across membrane of neuron alters
the PSP, producing either depolarization or
hyperpolarization of the postsynaptic membrane.
• It can be either excitatory or inhibitory pathway
 Excitatory pathway
• When an excitatory pathway is stimulated, a small
depolarization or excitatory postsynaptic potential
(EPSP) is recorded. This potential is due to the excitatory
transmitter acting on an ionotropic receptor, causing an
increase in cation permeability. Changing the stimulus
intensity to the pathway, and therefore the number of
presynaptic fibers activated, results in a graded change
in the size of the depolarization. When a sufficient
number of excitatory fibers are activated, the excitatory
postsynaptic potential depolarizes the postsynaptic cell
to threshold, and an all-or-none action potential is
generated.
Stimulation of excitatory neuron

Release of NT

Binding to postsynaptic membrane

N+ influx

Depolarization
 Inhibitory pathway

• When an inhibitory pathway is stimulated, the postsynaptic

membrane is hyperpolarized owing to the selective opening
of Cl– channels, producing an inhibitory postsynaptic
potential (IPSP) However, because the equilibrium potential
for Cl– is only slightly more negative than the resting
potential (-70 mV), the hyperpolarization is small and
contributes only modestly to the inhibitory action. The
opening of the Cl– channel during the inhibitory
postsynaptic potential makes the neuron "leaky" so that
changes in membrane potential are more difficult to
achieve. As a result, an excitatory postsynaptic potential
that evoked an action potential under resting conditions
fails to evoke an action potential during the inhibitory
postsynaptic potential
• Stimulation of inhibitory neuron

Release of NT

Binding to postsynaptic membrane

K+ efflux or Cl- influx

Hyperpolarization
 Neurotransmitter receptors

Neurotransmitters exert their effects on neurons by

binding to two distinct classes of receptor:
1. ligand-gated channels, or ionotropic receptors.
The receptor consists of subunits, and binding of
ligand directly opens the channel, which is an
integral parts of the receptor complex. Activation of
these channels typically results in a brief (a few
milliseconds to tens of milliseconds) opening of the
channel. Ligand-gated channels are responsible for
fast synaptic transmission typical of hierarchical
pathways in the CNS
2. Metabotropic receptors.
These are seven-transmembrane G-protei coupled
receptors. The binding of neurotransmitter to this
type of receptor does not result in the direct
gating of a channel. Rather, binding to the
receptor engages a G protein, which results in
the production of second messengers that
modulate voltage-gated channels
These might be either membrane-delimited or
diffusible second messengers pathway
 Sites of Drug Action
Virtually all the drugs that act in the CNS produce
their effects by modifying some step in chemical
synaptic transmission. These transmitter-
dependent actions can be divided into
presynaptic and postsynaptic categories.
1. presynaptic category
Drugs acting on the synthesi storage,metabolism,
and release of neurotransmitters fall into the
presynaptic category.
Post-synaptic category
In the postsynaptic region, the transmitter
receptor provides the primary site of drug
action. Drugs can act either as neurotransmitter
agonists, such as the opioids, which mimic
the action of enkephalin, or they can block
receptor function.
 CNS neurotransmitters
• More than 50 neurotransmitters have been
identified
• Most neurons make two or more NT
• Usually released in different stimulations
frquencies
• NT are classified by chemical structure and by
function
• 1. By chemical structure
• A)Biogenic amines:
• i)Catecholmaines: Dopamine, Norepinephrine,
Epinephrine.
• Ii)Indolamines: Serotonin, Histamine
• A) Amino acids: GABA, Glutamate, Glycine,
Aspartate
• C) Neuropeptides: vasopressin, oxytocin,
endorphins, enkephalines
• D) Purine nucleotides: adenosine, ATP
• E) Neurolipids: anandamide, 2-arachidonoyl
glycerol, ceramide
• F) Gases: NO, CO, H2S
• 2. By function
• Excitatory: Glutamate
• Inhibitory: GABA