CENTRAL NERVOUS
SYSTEM OVERVIEW
•One of the first to be discovered by primitive
humans
What did they discover?
•Nearly all drugs act on specific receptors—
modulate synaptic transmission.
•Important in the study of CNS physiology
•Mechanisms of diseases are discovered due to
the study of MOA of drugs
Integrative Function of the Nervous
System
•Cortex processes incoming
information before the command is
sent back to the effector organs.
•99% of the information is
discarded.
SYNAPSE
•Responsible for inhibition and
facilitation of impulses
•Has role in memory/storage of
information (temporal lobes).
PRE-, POST- & SYNAPTIC TERMINALS
•AP reaches pre-synaptic terminal and cause depolarization (Ca2+
enters the cell)
•Ca2+ triggers NT release from vesicles.
•NT binds to receptor sites on post synaptic membrane.
•Opening and closing of channels can cause change in post synaptic
membrane potential.
•AP propagates through the next cell and NT is inactivated or
transported back into the presynaptic terminal.
•Events in Presynaptic: AP, NT (Synthesis, Storage, Metabolism,
Release)
•Events in Post-synaptic: Degradation (target in Drug action)/
Reuptake
TYPES OF SYNAPSES
CHEMICAL
SYNAPSE
ELECTRICAL
SYNAPSE
•Uni/
Monodirectional
•Neurotransmitters
and neuropeptides
•Bidirectional
•Fuses with gap
junction channels—
readily enter and
exit
TYPES OF RECEPTORS
IONOTROPIC/
ION-GATED
METABOTROPIC/
2NDARY MESSENGERS
•Fast-acting
(milliseconds)
•Cation (+):
Sodium,
Potassium,
Calcium
-If it enters the
cell: causes
DEPOLARIZATI
ON
•Anion (-): Chloride
-If it enters the
cell: causes
HYPERPOLARIZ
ATIO N
(inhibition of
NT)
•Slow-acting (ms w/
delays)
•May last for
months (errors
may arise,
contributing to its
prolonged effect)
•Information is
relayed to the
second cell using
secondary
messengers such
as GPCR
Excitation and Inhibition of Post Synaptic Membrane
EXCITATION
•Opening of Na+ channels.
•Depressed conduction through chloride or potassium channels
•Result: Changes in internal metabolism
•Resting Membrane Potential
-RMP neurons: -65 or -70 mV
-RMP muscles: -90 mV
-PiSoCo: Potassium (in), Sodium (out), Chloride (out)
•Facilitation of Action Potential: -45 mV (change must be +20mV to
facilitate excitatory post synaptic potential)
INHIBITION
•Opening of Cl- channels.
•Increased conductance of K+ ions out of the neuron
•Activation of receptor enzymes
SPATIAL VS TEMPORAL SUMMATION
SPATIAL SUMMATION
•Multiple presynaptic neurons = More synapses firing to a postsynaptic
neuron = higher chance to reach an EPSP of +20 mV
TEMPORAL SUMMATION
•1 stimulation = 8 milliseconds (signal must reach +20mV within this
time limit)
•Single presynaptic neuron = Rapid/Sequential firing to postsynaptic
neuron = combined signals to reach +20mV
NEUROTRANSMITTERS (Small-
molecules) AND NEUROPEPTIDES
CLASS I
ACETYLCHOLINE
•First compound to be
identified as NT (mainly
excitatory) in the CNS.
•Locations:
-Motor cortex
-Basal ganglia
-Motor neurons that
innervate skeletal
muscles
-Pre- and post-
ganglionic neurons of
the ANS
•Mediated by a large family of
G-protein but also with ionic
properties (BOTH ionotropic
and metabotropic)
•Myasthenia gravis: NORMAL
ACh in the morni ng; LOW in
afternoon and night (Ptosis)
Recycling of ACh
•Made from choline and
acetyl CoA by choline
acetyltransferase
•Degraded by AChest erase
once bound to the receptor
in the post synaptic cleft.
•Choline is transported back
into the axon terminal and is
used again to make ACh.
Acetyl choline Recepto rs
•Nicotinic
-Ionotropic (rapid)
-Locations: NM J, CNS
axoaxonic synapse
•Muscarinic
-Metabotropic (slower)
CLASS II
AMINES
•Norepinephrine (NE)
•Epinephrine
•Dopamine
•Serotonin (5-HT)
•Melatonin
•Histamine
CLASS III
AMINO ACIDS
•GABA
•Glycine
•Glutamate
•Aspartate
CLASS IV
•ATP
•Arachidonic Acid
•Nitric Oxide
•Carbon Monoxide
NOREPINEPHRINE
•Synthesized from dopamine
•Cell bodies: found in pons,
medulla, thalamus
•Both excitatory and
inhibitory
•Function: raise BP
•Produced in locus coeruleus
Norepinephrine Pathway
•Dopamine to Norepinephrine:
Dopamine ß-hydroxylase
•Norepinephrine to
Epinephrine:
Phenylethanolamine N-methyl
transferase
Receptors
DOPAMINE
THREE MAJOR PATHWAYS
•Nigrostriatal System
-Motor control
(Extrapyramidal)
-Degradation: EPS
•Mesolimbic/Mesocortical
-Behavioral effects
-Indications: dopa
derivatives for
depression and anxiety
•Tuberohypophyseal Control
-Endocrine control
Dopamine Pathway
•Tyrosine to L-DOPA: Tyrosine
Hydroxylase
•L-DOPA to Dopamine: DOPA
carboxylase
Receptors
•D1-D5: G-protein mediated &
metabotropic
•D1-like
-Receptors: D1 and D5
-Location: Postsyna ptic
-Action : Increase
adenylate cyclase
-Destruction:
Hypokinetic
movement
•D2-like
-Receptors: D2, D3, and
D4
-Location: Pre &
Postsynaptic
-Action : Decrease
adenylate cyclase
GABA
•Major Inhibitory NT
•Location: whole CNS plus
spinal cord
•Pentameric structures that
are selectively permeable to
Cl-
•Both ionotropic and
metabotropic
•GABA-A:
-Ionotropic (fast)
-Cl- channel
-Postsynaptic
-Most used
•GABA-B
-Metabotropic (slow)
-K+ channel, G-protein
coupled, Ca2+
inhibition
-Postsynaptic and
presynaptic
autoreceptor
GABA Receptor Complex
•GABA site: activation =
influx of Cl- ions =
Hyperpolarization/
Inhibition of neuronal
activity
•Benzodiazepine site:
enhance GABA effect = more
Cl- channel opening= more
influx of Cl- ions = More
hyperpolarization/Inhibition
of neuronal activity
•Barbiturate site: increase
duration of Cl- channel
opening = further enhanced
GABA inhibitory effect
•Picrotoxin site: blocks Cl-
channel = counters GABA
inhibitory effect =
EXCITATORY
•Steroid site: modulation of
GABA receptor = contribute
to effects on sedation and
anesthesia
GLYCINE
•Inhibitory NT
•Simplest amino acid NT
•Location: restricted to spinal
cord and brainstem
•Pentameric structures that are
selectively permeable to Cl-
•Ionotropic (fast)
-Cl- channel
(hyperpolarization)
-Postsynaptic
-Most used
SEROTONIN
•5-hydroxytryptamine (5-
HT)
•Both ionotropic and
metabotropic
•Cell bodies are found in
raphe nucleus, pons, &
medulla
•Functions: Regulation of
emotions (mood), appetite,
body temp, vomiting,
sexuality, and sleep
Serotonin Pathway
•Try ptop han to 5-
hydroxytryptophan:
Try ptop han Hy drox yla se
•5- hydroxytrytophan to 5-
HT: AAA decarboxylase
Receptors
•Atleast 14 different subtypes
•5-HT3: Ionotropic (Cl-
channel)
•5-HT1B & 1D: Presynaptic
autoreceptors
(metabotropic)
•The rest are
METABOTROPIC!!!
GLUTAMATE
•Major Excitatory NT
•Location: high concentration
in synaptic vesicles
•Release: Ca2+ dependent
exocytosis
•Both ionotropic and
metabotropic
•Excitation: caused by
activation of ionotropic
NMDA, AMPA, and kainate
receptors
Glutamate Pathway
•Glutamine to Glutamate:
Glutaminase
•Glutamate packed into
vesicles by VGLUT.
•Released into synapse and
binds to AMPA and NMDA ion
channels and mGluR
(metabotropic) on the
postsynaptic cell.
•Glutamate is transported into
a nearby glial cell via a GLUT.
•Glutamate to Glutamine
(returned to the neuron):
Glutamine synthetase
NEUROPEPTIDES
Neuromodulators
•About 50 NPs exist
•Small molecule transmitters
that can co-exist and co-
released
•More potent than small
molecule transmitters
•May cause a more prolonged:
-Ca2+ channel
CLOSURE
-Metabolic change
-Alteration in
excitation and
inhibition of
receptors
•Synthesis: Ribosomes
•2 changes: splits into
neuropeptide and precursor
SUMMARY
•Mixed Type Receptors:
Acetylcholine, Serotonin,
GABA, Glutamate
•Metabotropic
Receptors (pre &
postsynaptic): NE,
Dopamine
•Ionotropic Receptors
(postsynaptic): Glycine
NEUROPEPTIDES
Pathway
•RER: NPs are synthesized as
large precursor proteins
•GA: Precursor proteins are
processed and packaged into
vesicles .
•Axonal transport: through the
cytoskeleton
•Cleavage of propeptides:
large precursors are cleaved
into active NP forms
•Small molecule transmitter:
NPs are often co-released with
SMNTs.
•NP release by exocytosis
•Retrograde transport: Excess
membrane elements are
transported back for recycling.
