Clinical pharmacology of CNS drugs, an introduction

1. Introduction to the pharmacology of CNS drugs
Domina Petric, MD

2. ION CHANNELS AND
NEUROTRANSMITTER
RECEPTORS
I.

3. VOLTAGE GATED
LIGAND GATED
The membranes of nerve cells contain
two types of channels:

4. Voltage-gated channels
• Voltage-gated channels respond to
changes in the membrane potential
of the cell.
• In nerve cells, voltage-gated
sodium channels are concentrated
on the initial segment and on the
axon.
• These channels are responsible for
the fast action potential, which
transmits the signal from cell body
to nerve terminal.

5. Voltage-gated channels
• There are many types of voltage-
sensitive calcium and potassium
channels on the cell body, dendrites
and initial segment, which act on a
much slower time scale and
modulate the rate at which the
neuron discharges.

6. Voltage-gated channels
• Some types of potassium
channels oponed by
depolarization of the cell result in
slowing of further depolarization
and act as a brake to limit further
action potential discharge.

7. Neurotransmitters bind on:
ionotropic receptors
metabotropic receptors

8. Ionotropic receptors
• The receptor consists of subunits.
• Binding of ligand directly opens the
channel.
• Channel is an integral part of the
receptor complex.
• These channels are insensitive or only
weakly sensitive to membrane potential.

9. Ionotropic receptors
• Activation of ionotropic receptors
results in a brief (a few milliseconds to
tens of milliseconds) opening of the
channel.
• Ligand-gated ionotropic channels are
responsible for fast synaptic
transmission typical of hierarchical
pathways in the CNS.

10. Metabotropic receptors
• These are seven-transmembrane G
protein-coupled receptors.
• Binding to the receptor engages a G
protein, which results in the
production of second messengers
that modulate voltage-gated
channels.

11. Membrane-delimited pathways
When G proteins interact with calcium
channels, they inhibit channel function:
presynaptic inhibition.
When these receptors are
postsynaptic, they activate potassium
channels: slow postsynaptic inhibition.

12. Diffusible second messengers
Example:
β adrenoreceptor
generates cAMP via the
activation of adenylyl
cyclase.

13. Metabotropic receptors
• Membrane-delimited actions occur
within microdomains in the membrane.
• Second messenger-mediated effects
can occur over considerable distances.
• The effects of metabotropic receptor
activation can last tens of seconds to
minutes.

14. Metabotropic receptors
Metabotropic
receptors predominate
in the diffuse neuronal
systems in the CNS.

15. THE SYNAPSE AND SYNAPTIC
POTENTIALS
II.

16. Synapses
• The communication between
neurons in the CNS occurs through
chemical synapses in the majority
of cases.
• Electrical coupling between
neurons may play a role in
synchronizing neuronal discharge.

17. Propagation of action potential
• 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.
• The increase in intraterminal calcium
concentration promotes the fusion of
synaptic vesicles with the presynaptic
membrane.

18. Propagation of action potential
• The transmitter contained in the vesicles
is released into the synaptic cleft and
diffuses to the receptors on the
postsynaptic membrane.
• Binding of the transmitter to its receptor
causes a brief change in membrane
conductance (permeability to ions) of the
postsynaptic cell.

19. Propagation of action potential
The time delay from the
arrival of the presynaptic
action potential to the
onset of the postsynaptic
response is 0,5 ms.

20. EPSP
When an excitatory pathway is stimulated,
a small depolarization or excitatory
postsynaptic potential (EPSP) is recorded.
Excitatory transmitter is acting on an
ionotropic receptor causing an increase in
cation permeability.
When sufficient number of excitatory fibers
are activated, the EPSP depolarizes the
postsynaptic cell to threshold: all-or-none
action potential is generated.

21. IPSP
When an inhibitory pathway is stimulated,
the postsynaptic membrane is
hyperpolarized owing to the selective
opening of chloride channels: inhibitory
postsynaptic potential (IPSP).
Equilibrium potential for chloride is only
slightly more negative than the resting
potential (-65 mV): the hyperpolarization is
small and contributes only modestly to the
inhibitory action.

22. IPSP
• The opening of the chloride channel
during the inhibitory postsynaptic potential
makes the neuron leaky.
• Changes in membrane potential are more
difficult to achieve.
• This shunting effect decreases the
change in membrane potential during the
excitatory postsynaptic potential.

23. Presynaptic inhibition
• Axoaxonic synapses reduce the amount
of transmitter released from the terminals
of sensory fibers.
• Presynaptic inhibitory receptors are
present on almost all presynaptic
terminals in the brain.
• Axoaxonic synapses are restricted to the
spinal cord.

24. CELLULAR ORGANIZATION OF
THE BRAIN
III.

25. Cellular organization of the brain
HIERARCHICAL SYSTEMS
NONSPECIFIC OR DIFFUSE
NEURONAL SYSTEMS

26. Hierarchical systems
Hierarchical systems include all the pathways
directly involved in sensory perception and
motor control.
The pathways are generally clearly delineated,
being composed of large myelinated fibers that
can often conduct action potentials at a rate of
more than 50 m/s.

27. Hierarchical systems
• Information in hierarchical systems is
typically phasic and occurs in bursts of
action potential.
• In sensory systems, the information is
processed sequentially by successive
integrations at each relay nucleus on its
way to the cortex: a lesion at any link
incapacitates the system.

28. Two types of cells are:
RELAY OR PROJECTION
NEURONS
LOCAL CIRCUIT
NEURONS

29. Projection neurons
• The projection neurons form the
interconnecting pathways and transmit
signals over long distances.
• The cell bodies are relatively large.
• Their axons emit collaterals that arborize
extensively in the vicinity of the neuron.
• These neurons are excitatory.

30. Projection neurons
Synaptic influence of projection neurons
involves ionotropic receptors.
Their influence is very short-lived.
The excitatory transmitter is
GLUTAMATE.

31. Local circuit neurons
• Local circuit neurons are smaller
than projection neurons.
• Their axons arborize in the
immediate vicinity of the cell body.
• Most of these neurons are inhibitory:
they release GABA or glycine.

32. Local circuit neurons
• They synapse primarily on the cell body of
the projection neurons.
• They can also synapse on the dendrites
of projection neurons as well as with each
other.
• Two common types of pathways are
recurrent feedback pathways and feed-
forward pathways.

33. Local circuit neurons
• A special class of local circuit neurons are
axoaxonic synapses on the terminals of
sensory axons in the spinal cord.
• In the retina and olfactory bulb, local
circuit neurons may lack an axon and
release neurotransmitter from dendritic
synapses in a graded fashion, in the
absence of action potential.

34. Nonspecific (diffuse) systems
Neuronal systems that contain
one of the monoamines:
• norepinephrine
• dopamine
• 5-hydroxytryptamine
(serotonin)

35. Example: noradrenergic neurons
Noradrenergic cell
bodies are found
primarily in a compact
cell group locus
caeruleus.

36. Noradrenergic neurons
• These axons are fine and unmyelinated.
• They conduct very slowly at about 0,5 m/s.
• The axons branch repeatedly and are
extraordinarily divergent.
• Branches from the same neuron can
innervate several functionally different
parts of the CNS.

37. Noradrenergic neurons
• In the neocortex, these fibers have a
tangential organization and can
monosynaptically influence large areas
of cortex.
• The pattern of innervation by
noradrenergic fibers in the cortex and
nuclei of the hierarchical system is
diffuse.

38. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.