Transcript Fundamentals of Psychopharmacology

Neurotransmission and
Signal Transduction
Paul Glue
Objectives
•Review aspects of chemical transmission and intracellular signalling in
the brain
•Role of neurotransmitter/signal transduction abnormalities in selected
neurological/psychiatric disorders
–Rational pharmacology for nervous system disorders
–Prediction of side-effect profile
Basic Neurotransmission
2…releasing neurotransmitter
into synapse...
1: Presynaptic neuron fires...
3…transmitter interacts
with a post-synaptic receptor
which may...
4…activate second
messenger pathways….
6…which may lead to
cell firing; inhibition of
firing; genome activation,
peptide production etc….
5….open an
ion channel….
7…which may translate into perception; memory; emotion; autonomic homeostasis; endocrine response etc….
8…and in pathological states may translate into depression, seizures, neurodegeneration, etc….
Neurotransmission
• Based on anatomy of neuronal pathways
• Based on diffusion of chemical signals
– signalling may extend beyond the site of release to adjacent synapses
• Based on speed of response
– fast: glutamate (+); GABA (-)
– slow/modulatory: serotonin, norepinephrine, neurohormones
• Based on neuronal responses
– chemical signal from proximal neuron may produce :
• nerve firing/inhibition of firing
• increased activity of second messengers
• gene transcription
• increased/decreased receptor density/sensitivity (synaptic plasticity)
• increased/decreased synaptic connections
Characteristics of 4 Major Receptor Types
Receptor
Ligand-gated
ion channel
Timescale
Effector
Milliseconds Channel
Coupling
Example
Direct
Nicotinic
AChR
G-proteinSeconds
coupled receptor
Channel/
enzyme
G-protein
Muscarinic
AChR
Kinase-linked
receptor
Enzyme
(tyrosine
kinase)
Direct or
indirect
Insulin
Gene
transcription
Via DNA
Thyroid,
estrogen
Minutes
Nuclear receptor Hours
Ligand-Gated Ion Channels
- Agonist-regulated, ionspecific, membrane
spanning channels
- Passage of ions alters
membrane potential/ionic
composition
- Made up of subunits
Examples: Nicotinic
cholinergic, GABA-A,
glycine, glutamate,
aspartate, 5-HT3 receptors
G-Protein Coupled Receptors
7 transmembrane-spanning helices
- Associated with trimeric GTPbinding regulatory proteins
- Agonist binding to extracellular
domain
- GTP activates G-protein, which
then activates specific effector
proteins
- Individual cells can express up to
20 GPCRs
Examples: NE, 5-HT, DA, histamine,
opioids, (>750)
-
Video clip
Intracellular Signal Transduction
Arrestin binds to the phosphorylated
C-terminal tail
Arrestin
binds
to clathrin
(vesicular
protein)
Receptor-G
protein
interaction
is prevented
G-Protein
A
G-protein
complex
receptor
is kinase
activated
phosphorylates
by
a
c-Src
phosphorylates
endocytosis
Activated
Gα
and β/γ
subunits
receptor
activity
isdynamin;
haltedreceptor
Agonistand
binds
to
G-Protein-coupled
GDPGTP
the
receptor’s
switch
C-terminal
in Gα tail
subunit
of
receptor
commences
move
to regulate
effectors
c-Src
(tyrosine
kinase)
binds
to arrestin
γ
Gα
β
VIDEO
GTP
Receptor may be reinserted in membrane…
β β γ γ β γ Gα Gα
Gα
Dyn
DynDyn
Effector
Effectoris complete.
Endocytosis
Dyn
Dyn
P P
Gα Effector
GTP
GDP
GTP
c-Src P P
P
P
GTP GTP
dissociates
Or mayAgonist
remain in
vesicle inand
Receptor
is dephosphorylated
cytoplasm
in an inactive
state….
P
G
Gαs:  adenylyl cyclase
c-Src effects on:
GDP
ArrestinAdenylyl cyclase
GRK Gαi:  adenylyl cyclase
Phospholipase C Gαo:  Ca++ currents
P
PI-3-kinase
Gαq:  phospholipase C
c-Src
GTP
Or may be degraded by lysosomes
ArrestinInward-rectifier
Gα13:  RHO GTP exchange
K+ currents
catalyst
GRK
Arrestin
P
P
Arrestin
c-Src
Intracellular Signaling
• Post-receptor signal transduction occurs via networks of
signaling proteins (2o and 3o messengers)
– transform multiple external stimuli into appropriate cellular
responses.
• Molecules in this network form ordered biochemical
pathways
– signal propagation occurs through the sequential protein-protein
and small molecule-protein interactions.
• Signaling components are organized into macromolecular
assemblies (adapter proteins)
– organize signaling pathways into distinct functional entities
– critical for efficiency and specificity of signaling
– various levels of complexity (simple to complex multi-domain
proteins)
Signal Amplification Cascade
Transmitter
Transmitter activates receptor
Receptor activates G-protein
GTP
G-protein stimulates adenylyl
cyclase to convert ATP to cAMP
GDP GTP
GDP
AC
ATP
cAMP
PKA
cAMP
PKA phosphorylates
K channels
GTP
AC
ATP
cAMP activates
protein kinase A
GDP
AC
ATP
cAMP
PKA
cAMP
cAMP
PKA
cAMP
Synaptic Plasticity
• Historical View:
– Synapses and overall neuronal structure relatively fixed.
– Learning and other mental processes occurred via adjusting the threshold
and firing rate between the synapses
• Contemporary View:
– Neuronal signaling and responsiveness are highly dynamic and adaptive
– Changes may occur in response to developmental or experiential input
– Changes may occur at multiple levels (molecular, transcriptional, cellular)
Some Of The Major Intracellular Signalling Pathways
Involved In Regulating Neural And Behavioral Plasticity
Transduction at multiple levels - Vision
Environmental stimulus
Specific receptor and
second messenger
Sensory nerve
Primary cortex
Light waves
G-protein associated with rhodopsin
in rods/cones
Depolarization of neurons in optic N
Occipital cortical neurons
Secondary cortices
Localized processing of specific
categories (shape, movement, color,
faces)
Organization of images in temporal
lobes. Memory and affective input
DLPFC (executive functioning,
planning, decision making)
Association cortices
Higher processing
Examples of Dopaminergic Plasticity
– Desensitization (agonists):
• Rapid loss of euphoric effects of cocaine
• Loss of efficacy of PD treatment over time (?or due to
disease progression)
– Sensitization (agonists)
• Increased dendrite density in N Acc, PFC after chronic
cocaine/amphetamine
– May explain phenomenon of behavioral sensitization
– Sensitization (antagonists)
• Tardive dyskinesia possibly caused by striatal D2
hypersensitivity, following chronic neuroleptic treatment
NE/5HT plasticity
– Desensitization
• Short term use of antidepressants
– Reduction of incidence/severity of earl;y side effects (GI
symptoms, insomnia, anxiety)
• Chronic administration of antidepressants
– Postsynaptic receptors – therapeutic
• Abrupt antidepressant withdrawal
– Presynaptic autoreceptors – possible cause of withdrawal
symptoms after stopping antidepressants
– Synaptic/neuronal growth
• Serotonin depletion reduces synaptic density
•  hippocampal neurogenesis by antidepressants
•  dendritic growth by lithium
Other plasticity examples…
• Tolerance to alcohol and ….
• Alcohol withdrawal and ….
• Acute BDZ tolerance (waking post O/D) vs
chronic tolerance
• Tolerance to opioids
• Hypertensive rebound after stopping
clonidine
Conclusions
• Chemical neurotransmission and subsequent signal transduction
are the main processes for neuronal communication
– Adaptive, plastic process
• Role of specific neurotransmitters in selected nervous system
disorders
– Biochemical basis for neurological and psychiatric disorders
– Choice of rational pharmacotherapy for nervous system disorders
– Also may predict side-effect profile of existing and new treatments
• Range of potential therapies will expand as our understanding of
central transmission/signal transduction becomes more
sophisticated