This document provides an overview of basic principles of drugs affecting the central nervous system (CNS). It discusses the cellular organization of the brain including neurons and supporting cells. It describes the blood-brain barrier and how it impacts drug delivery to the CNS. It also outlines neuronal excitability and ion channels, processes involved in synaptic signaling, and various central neurotransmitters including amino acids, acetylcholine, monoamines, peptides, purines, and neuromodulatory lipids.

1. Basic Principles of Drugs
Affecting the CNS
Dr. M. Ahsan (MBBS, MD)

2. Introduction
• Drugs acting on the CNS are invaluable for various conditions:
• Anxiety • Depression • Mania • Schizophrenia
• Pain • Fever • Movement
disorders
• Insomnia
• Eating disorders • Nausea • Vomiting • Migraine
• Recreational use of some CNS-acting drugs can lead to dependence

3. Cellular
organization of the
brain
The CNS is made up of: 1. Neurons 2. Supporting cells
The sites of inter-neuronal connections is termed as “synapse”
The neurons are electrically active cells that have ion channels.
They conduct nerve impulses which triggers the release of
“neurotransmitters”
Neurotransmitters are stored in synaptic vesicles in the neurons
The neurotransmitters released act on neighbouring cells via
“receptors”
The support cells include neuroglia, vascular elements and CSF-
forming cells

4. Blood-Brain Barrier (BBB)
• The BBB separates the capillary carrying blood from the CNS
• It is an obstacle for drug delivery to the CNS
• The BBB is deficient at the chemo-receptor trigger zone (CTZ)
• Inflammation of the meninges (as in meningitis) increases permeability of
the BBB
Exception: lipid-soluble drugs can diffuse freely across the BBB and can
accumulate in the brain

5. Neuronal excitability & Ion channels
• Voltage gated ion channels on neurons open in response to an action
potential
• Ligand gated channels open in response to binding of ligands
• Important cations: Na, K, Ca
• Important anions: Cl

6. Neuronal excitability & Ion channels
• Na channels: Increase in permeability of Na causes depolarization
• K channels: Increase in permeability of K causes hyperpolarization
• Ca channels: changes in intra-cellular concentration of Ca affects multiple
processes and is important for release of neurotransmitters
• Cl channels: activation of Cl channels decreases neuronal excitability and
inactivation of these channels can cause hyperexcitability

7. Identification of Neurotransmitters
• Neurotransmitters
are endogenous
chemicals in the
brain that modulate
signalling across a
chemical synapse
The transmitter
must be present
in the pre-
synaptic terminal
of the synapse
The transmitter
must be released
from the pre-
synaptic terminal
in adequate
quantities
following an AP
The effect of
experimental
application of
transmitter must
mimic
stimulation of
pre-synaptic
terminal
There should be
a mechanism
present which
terminates the
action of the
transmitter

8. Neurotransmitters
Many nerve terminals contain multiple transmitters and co-existing substances
that act either:
 Jointly on the post-synaptic membrane
OR
 Presynaptically to affect release of transmitter from the pre-synaptic terminal

9. Processes involved in synaptic signalling
Neurotransmitter synthesis
Neurotransmitter storage
Neurotransmitter release
Neurotransmitter
recognition
Termination of action

10. Processes involved in synaptic signalling
1. An influx of Ca2+ during an AP triggers (2)
2. Exocytosis of synaptic vesicles that stores
neurotransmitters
Neurotransmitter interact with receptors (3) or (4) on post-
synaptic membrane or (5) on pre-synaptic receptor
3. Ion channel coupled receptor
4. GPCRs
5. Pre-synaptic receptor can inhibit or enhance
neurotransmitter release
Released neurotransmitter is inactivated by (6) or (7) or (8)
6. Reuptake into nerve terminal (eg. NE)
7. Enzymatic degradation (eg. Ach)
8. Uptake and metabolism by glial cells (eg. Glutamate)

11. Termination of neurotransmitter action
• Mechanisms to
terminate the
actions of released
neurotransmitters
are essential for
maintaining the
balance of neuronal
signalling
3.Minorpathway
2.Reuptake
1.Enzymaticdegradation
Conversion
of the
transmitter
into an
inactive
compound
via
enzymatic
degradation
Eg. Ach is
hydrolyzed
by
acetylcholine
sterase to
choline and
acetate
Clearance of
transmitter
by transport
proteins
present on
the pre-
synaptic
membrane
Eg. NET,
SERT and
DAT remove
NE,
serotonin
and
dopamine
respectively
Slow
diffusion of
transmitter
away from
synapse and
subsequent
degradation

12. Central neurotransmitters
• Neurotransmitters can be classified on the basis of chemical structure
into:
• Amino acids
• Acetylcholine
• Monoamine
• Neuropeptides
• Purines
• Lipids
• Gases

13. Central neurotransmitters: Amino acids
• Glutamate
• Aspartate
• GABA
• Glycine
• β-alanine
• Taurine
Excitation
Inhibition
The CNS contains high
concentrations of GABA (γ-amino
butyric acid) and glutamate, which
alters neuronal firing

14. GABA
• GABA is the main inhibitory neurotransmitter in the CNS
• GABA acts by binding to and activate receptors on both pre- and
postsynaptic membranes.
GABA-A receptors (most prominent subtype): ligand-gated Cl– channels
GABA-B receptors : GPCRs

15. GABA • GABA-A receptors are
pentameric and assembled
around a central Cl-channel
• GABA-A receptors are the site
of action of benzodiazepines,
barbiturates, ethanol,
anesthetic steroids, and
volatile anesthetics, among
others
• These drugs are used to treat
epilepsy, Huntington disease,
addictions and sleep disorders

16. Glutamate
• Glutamate is the most abundant excitatory neurotransmitter
• Glutamate acts though receptors that are classified as either
 ligand gated ion channels (ionotropic)
GPCRs
• Ionotropic glutamate receptors were historically divided into three classes,
each named for its preferred synthetic ligand:
NMDA receptors
AMPA receptors
KA receptors.

17. Central neurotransmitter: Acetylcholine (Ach)
• Acetylcholine was the first neurotransmitter to be discovered
• Plays a primary role in the :
Autonomic nervous system (ganglionic transmission, parasympathetic
nerve endings)
Peripheral nervous system (neuromuscular junction)
• ACh interacts with two broad classes of receptors:
Nicotinic receptors (ligand-gated ion channels)
Muscarinic receptors (GPCRs)
The degeneration of
cholinergic pathways is
a hallmark of
Alzheimer disease

18. Acetylcholine (Ach)
AChE
ACh
N M
Choline
Acetate
Ch
ACh
ChAT
M
-
ACh is synthesized by choline
acetyltransferase and stored
in the nerve endings.
Following release and
receptor activation, it is
degraded by
Acetylcholinesterase

19. Central neurotransmitters: Monoamines
• Monoamines are neurotransmitters whose structure contains an amino
group connected to an aromatic ring by a two-carbon chain.
• Monoamines regulate neurotransmission that underlies cognitive
processes, including emotion.
• Drugs that affect monoamine signaling are used to treat depression,
schizophrenia, and anxiety, and Parkinson disease.
Monoamines include dopamine (DA), Norepinephrine (NE),
Epinephrine (EPI), histamine and serotonin (5HT)

20. Dopamine
• Dopamine, NE, and EPI are catecholamine neurotransmitters
• DA is the predominant catecholamine in the CNS
• There are three major DA-containing pathways in the CNS:
nigrostriatal
mesocortical/mesolimbic
tuberoinfundibular
Dopamine plays a role in motivation and
reward (most drugs of abuse increase DA
signaling), motor control, and the release of
various hormones

21. Dopamine
• Dopamine acts on five distinct GPCRs grouped into two subfamilies:
D1-like receptors (D1 and D5)
D2-like receptors (D2, D3, and D4)
DA-containing pathways and receptors have been implicated in the
pathophysiology of schizophrenia and Parkinson disease

22. Norepinephrine (NE)
• NE is an endogenous neurotransmitter for the α and β adrenergic receptor
subtypes that are present in the CNS; all are GPCRs
• There are relatively large amounts of NE within the hypothalamus and in
certain parts of the limbic system

23. Epinephrine (Epi)
• Epinephrine-containing neurons are found in the medullary reticular
formation and make restricted connections to pontine and diencephalic
nuclei, eventually coursing as far rostrally as the paraventricular nucleus of
the thalamus. Their physiological properties have not been unequivocally
identified.

24. Histamine
• Histamine is a monoamine neurotransmitter in the CNS in addition to its
well-known physiological function in immune and digestive responses in
the periphery.
• The histaminergic system is thought to affect arousal, body temperature,
and vascular dynamics
• Histamine acts through 4 receptor subtypes: H1, H2, H3 and H4

25. Serotonin
• There are diverse pathways mediating serotonin signaling that play a role in
• modulating mood, depression, anxiety, phobia, and GI effects.
• Serotonin receptors are targets for both therapeutic and recreational
(hallucinogenic) drugs

26. Central neurotransmitters: Peptides

27. Central neurotransmitters: Purines
• Adenosine, ATP, UDP, and UTP have roles as extracellular signaling
molecules.
• ATP is also a component of many neurotransmitter storage vesicles and is
released along with transmitters.

28. Central neurotransmitters: Neuromodulatory
lipids
• In the 1960s, THC or tetrahydrocannabinol was identified as a psychoactive
substance in marijuana.
• This led to the discovery and cloning of the two cannabinoid receptors
• Receptor subtypes: CB1 and CB2
• Marijuana is known to stimulate appetite via activation of the CB1
receptor
• CB1 antagonists are being tested for the treatment of obesity.

29. Thank you

30. References
• Goodman & Gillman’s: The Pharmacological Basis of Therapeutics,
13th edition. New York: McGraw-Hill, 2018
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.