BIOM*3090 Drugs Acting on the CNS

Pharmacological Organization of the CNS

Cellular Organization of the CNS

-individual cells in the CNS are organized in circuits which

coordinate function
-the circuits vary in size & complexity ranging from 2 neuron
reflex arcs to complex networks of cells controlling complex
functions (eg. sensation, motor activity, mood)

MAJOR REGIONS OF THE BRAIN

Cerebral cortex

Limbic system
Diencephalon

Cerebellum
Midbrain

Brain stem

Spinal cord

Major Anatomical Subdivisions of the Brain

Region Characteristics
Cerebral cortex • largest region
• processing of information (sensory, motor &
associational)
• integration of functions (somatic & vegetative)

Limbic system • variety of structures beneath cerebral cortex

• integration of emotional state with motor &
visceral activities

Cerebellum • behind the cerebral hemispheres

• provides complex sensorimotor coordination

Midbrain & brain stem • beneath cerebrum & cerebellum at base of brain
• relay of information from cerebrum & limbic
system to spinal cord
• provide central integration of essential reflexes

Spinal cord • extends caudally from brain stem

• receives, sends & integrates sensory & motor
information

70
Pharmacology 98-309 Drugs Acting on the CNS

Neurotransmitters of the CNS

Characteristics of neurotransmitters:

-neurotransmitters are the substances neurons use to communicate with each

other.
-neurotransmitters are synthesized by the neuron, present in nerve terminal
and are released on nerve stimulation
-exogenous application of neurotransmitter or drug agonists produces a
predictable response
-in the CNS there is a heterogeneous group of compounds ranging from
small amino acids to large peptides

Classification of CNS Neurotransmitters According to Function

Neurotransmission in the CNS involves either transmitters with
unique structures with no other known function as well as many
compounds with other important functional roles in other tissues
1. Neurotransmitter function only
eg. ACh, NE, dopamine, GABA, & some peptides
(neuropeptide Y, substance P)
-no other known function
2. Hormones
eg. epinephrine, histamine, serotonin & all other peptides
-also have important hormonal function in lung, GI tract etc.

3. Amino acids
-also important in formation of peptides & proteins

4. Nucleotides
-also involved in energy metabolism

Classification of Central Neurotransmitters According to Chemical Structure

1. Amino Acids
a) Inhibitory or neutral (glycine, GABA)
b) Excitatory or acidic (glutamate, aspartate)

2. Biogenic Amines
a) acetylcholine
b) monoamines:
• norepinephrine
• dopamine
• serotonin (5-hydroxytryptamine)
3. Peptides

4. Nucleotides and nucleosides (adenosine & ATP)

71
BIOM*3090 Drugs Acting on the CNS

1. Amino acids

-high concentration in CNS

-potent modifiers of neuronal excitability
-natural toxins which antagonize ion channels have been used to
study function

a) Inhibitory (neutral) →↓ neuronal firing

• glycine →↑ membrane permeability to Cl-
eg. strychnine antagonizes glycine in inhibitory
Renshaw cells in spinal cord → convulsions

• gamma amino butyrate (GABA)

-receptors open Cl- channels
eg. picrotoxin antagonizes GABA receptors
→ convulsions

b) Excitatory (acidic) →↑ neuronal firing

• glutamate
• aspartate

Activation of receptors by excitatory a.a. affects either:

2+
i) Cation-selective channels (eg. Na+, K+, or Ca )
ii) Intracellular enzymes (eg. phospholipase C or adenylyl
cyclase)
-aspartate receptor may play a role in learning & memory
-i.e. mostly NMDA receptors (N methyl D aspartate)
-selectively blocked by dissociative anesthetics (ketamine) and
hallucinogenic drugs (phencyclidine)

2. Biogenic Amines

a) acetylcholine
-most CNS responses mediated by muscarinic receptors
-most responses are slow excitation
-play an important role in cognitive functions ie. memory
-Alzheimer dementia associated with loss of cholinergic neurons

b) Monoamines
-present in small localized amounts in CNS
-site of action of many drugs

CNS stimulants act on catecholamine system

eg. cocaine → blocks reuptake of dopamine & NE
eg. amphetamine → causes release and blocks reuptake of
dopamine & NE
i) Norepinephrine
-α and β receptors
-found diffusely throughout CNS
-mostly in reticular formation (in core of medulla, pons &
midbrain), responsible for arousal of cerebral cortex, control
of vital functions, vomiting & swallowing etc.
-both excitatory and inhibitory
-excitatory transmission → behavioural processes
eg. attention, arousal
72
Pharmacology 98-309 Drugs Acting on the CNS

ii) dopamine
-slow inhibitory action
-especially important in:
• substantia nigra (in midbrain)
eg. antiparkinsonism drugs (levadopa)
• limbic cortex (responsible for emotional activity)
eg. antipsychotic drugs (phenothiazines)

iii) serotonin (5-hydroxytryptamine)

-found diffusely throughout CNS
-most pathways in pons & brain stem
-strongly inhibitory
-controls regulatory functions including sleep,
temperature, appetite & neuroendocrine control

3. Peptides
-many peptides affect animal behavior and activity of individual neurons
-Examples:

opioid peptides K substance

(eg. enkephalin, endorphins) neurotensin
somatostatin adrenocorticotropic
angiotensin II hormone (ACTH)
vasopressin insulin & glucagon
bradykinin neuropeptide Y
substance P oxytocin

Differences between peptides and other neurotransmittors:

• synthesized in the cell body with axonal transport to nerve
terminal
• no reuptake or enzyme degradation

4. Nucleotides and nucleosides

eg. adenosine & ATP

Summary of Nonpeptide Neurotransmitters in CNS

Transmitter Location Receptors Mechanism

ACh All levels Muscarinic M Excitatory
1
Renshaw cell synapse Nicotinic Excitatory
Dopamine All levels (diffuse D and D Inhibitory
1 2
neuronal systems)
GABA Spinal interneurons GABA & GABA Inhibitory
A B
Glutamate/ Relay neurons at all NMDA, AMPA, ACPD Excitatory
Aspartate levels
Glycine Spinal interneurons & Taurine, β-alanine Inhibitory
in brain stem
Serotonin From midbrain & pons 5-HT1 (mostly) Inhibitory
to all levels 5-HT2, 5-HT3, 5-HT4 Excitatory
NE From pons & brain α1, β1 Excitatory
stem to all levels α 2 , β2 Inhibitory
NMDA: N-methyl-D-aspartate
AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-proprionate
ACPD: trans-1-amino-cyclopentyl-1,3-dicarboxylate

73
BIOM*3090 Drugs Acting on the CNS

Some similarities & differences in synthesis, storage and

degradation of neurotransmitters in the brain

1. Synthesis in the cell body (peptides), nerve terminal cytosol (ACh, GABA),
or vesicle (NE)

2. Storage of transmitter (ACh, GABA, peptide) or precursor (NE) into vesicles

3. Inactivation by enzymatic hydrolysis (ACh), active reuptake (NE, serotonin),

nonspecific uptake (GABA), or diffusion (peptide)

4. Reuse of transmitter (NE, GABA) or hydrolysis product (ACh) or neither

(peptide) for further transmitter synthesis

5. Control of synthesis by substrate availability (ACh) or enzyme activity (NE,

GABA, peptide)

Synaptic Potentials in CNS

Excitatory & Inhibitory Systems
-net effect of activation of one neuronal system is to ↑ or ↓ activity of
another neuronal system
-depends on neurotransmitter released & types of receptor on target cell
-neuronal systems have different levels of tonic activity
-ie. neurons can generate their own rhythmic impulse activity
(ie. pacemaker cells)
-this activity can be ↑ or ↓ by excitatory or inhibitory control systems
respectively

For example:
A drug which →↓ neuronal activation can cause activation by ↓ inhibitory input

OR
A drug which →↑ neuronal activation can inhibit by ↑ inhibitory input

∴ depressant drugs can → excitation

stimulant drugs can→ sedation

eg. ethanol (a depressant) → initial stimulation due to depression

of inhibitory control system

ALSO
-variations in activity of inhibitory and excitatory central systems
alters effects of centrally acting drugs

eg. anesthetics are less effective in hyperexcitable patients

eg. stimulants are less effective in sedated patients
AND
-co-administration of other stimulant and depressant drugs have
generally additive responses on CNS
eg. ethanol & barbiturates → fatal depression

74
Pharmacology 98-309 Drugs Acting on the CNS

Mechanisms:

a) Excitatory:
-excitatory transmitter →↑ Na+/K+ permeability
→ depolarization of post-synaptic cells → action potential

b) Inhibitory:
-inhibitory transmitter →↑ permeability to Cl-
→hyperpolarization → no AP

CELLULAR ORGANIZATION OF THE CNS

The CNS contains two types of neuronal systems hierarchical and diffuse.

System
Parameter Hierarchical Diffuse
Location -in brain nuclei & cerebral cortex -affects vast areas of CNS
simultaneously & uniformly

Neuron type -highly specific, orderly & directed -affects may brain regions
flow of information simultaneously & uniformly

-large, myelinated, rapidly conducting -axons are fine & branch to

fibers synapse on many cells
Functions -major sensory & motor functions -integrated brain functions
(ie. mood, arousal, emotion,
motivation)

Transmitter -excitatory transmitters -transmitters are often amines

(asparate, glutamate) (norepinephrine, dopamine,
serotonin) or peptides

-small inhibitory interneurons

(GABA or glycine)

Interruption -dramatic loss of information transfer -subtle changes ie. modulation of

Drug effects -well-defined effects
eg. anticonvulsants: block
hyperactivity of motor & sensory
systems
eg. analgesics: block transduction of
sensory pain information
global aspects of CNS function
-less specific & ill-defined effects
-cause subtle modifications
throughout the whole system
eg. drugs which treat psychosis,
depression, anxiety & sleep
disorders

Sites of Action of CNS Drugs

• Neurons in the CNS communicate through chemical synapses.
• Almost all CNS drugs modify chemical synaptic transmission
• A few agents (ie. general anesthetics & alcohol) may have nonspecific actions on membranes
• Selectivity based on the fact that different pathways utilize different transmitters

75
BIOM*3090 Drugs Acting on the CNS

Synthesis
Reuptake Nerve terminal
Metabolism
Storage

Receptor Release
Degradation
Post-synaptic cell

Response

1. Action potential in presynaptic fiber

presynaptic

2. Synthesis of transmitter
3. Storage
4. metabolism
5. release
6. reuptake
7. degradation
postsynaptic

8. receptor binding
9. receptor stimulation
10. response

Most neurotransmitters are synthesized locally in nerve terminals. The exception

is peptide neurotransmitters which are synthesized by ribosomes in the cell body
and are transported down axon to nerve terminals.

Selected Examples of Mechanisms of Drug Action in CNS

1. Presynaptic

• ↓ storage of cerebral monoamines

eg. reserpine (sedative)

• ↑ catecholamine release from adrenergic synapses

eg. amphetamine (stimulant)
• blockade of reuptake of catecholamines
eg. cocaine

2. Postsynaptic

-neurotransmitter agonists
eg. opiates mimic enkephalin

-neurotransmitter antagonists
eg. strychnine blocks glycine inhibitory receptor
76
Pharmacology 98-309 Drugs Acting on the CNS

Receptors are coupled to:

a) Ion channels

-molecular pores in the membrane that allow specific

species of ions to pass; exist in open & closed states
-permeability changes in channels are main components of
action potentials
-receptor activation opens ion channels
-drugs can block ion channels
eg. barbiturates block excitatory ion channels

b) Enzymes
-receptor activation→ metabolic changes in post-synaptic
cell via second messenger systems
eg. methylxanthines (theophylline & caffeine) ↑ cAMP by
blocking its metabolism
→ prolonged effect of receptor stimulation in post-synaptic
cell

Targets for Drugs acting on the CNS

Actions Molecular Target Class of Drugs

General Membrane lipids General anesthetic drugs

Neuron-specific -Na+ channels Local anesthetics
-Ca2+ channels Ca2+ channel blockers

Transmitter-specific -opioid receptors -opioid analgesics/antagonists

-GABA receptors -benzodiazepines
-GABA receptors -barbiturates
-adrenergic receptors -clonidine
-histamine receptors -antihistamines
-dopamine receptors -antipsychotic drugs
-adenosine receptors -caffeine
-monoamine oxidase -MAO inhibitors
-dopamine synthesis -L-dihydroxyphenylalanine
-NE reuptake -tricyclic antidepressants
-serotonin reuptake -serotonin reuptake inhibitors
-dopamine reuptake -amantidine
Signal-specific -Phosphatidyl inositol -lithium carbonate
breakdown
-cAMP breakdown -caffeine

Transmitter-specific drugs are more commonly used, have greater

specificity of action & have fewer side-effects

77