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Overview CNS Chemical
TransmissionTCM
INTI University
Tay Ju Lee MD
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Objectives
Chemical transmission overview
Glutamate
GABA
Noradrenaline
Dopamine
Serotonin
Acetylcholine
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Categories of Neurotransmitters
Excitatatory Amino Acids Glutamate
Inhibitory Amino Acids
GABA & Glycine Monoamine Mediators & Pathways
Noradrenaline
Dopamine
5 HT
Acetylcholine
Others
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Question to keep in mind
Whats the transmitter?
What & Where are the receptors?
How do they work?
What do they do in CNS?
What are clinically important drugsassociated with the receptor?
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Chemical transmission
The basic processes of synaptictransmission in the CNS areessentially similar to those
operating in the periphery
Glial cells, particularly astrocytes,
participate actively in chemicalsignalling, functioning essentially
as 'inexcitable neurons'.
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Definitions
Neurotransmission neurotransmitters are released by presynaptic
terminals and produce rapid excitatory orinhibitory responses in postsynaptic neurons
Neuromodulation neuromodulators are released by neurons and by
astrocytes, and produce slower pre- orpostsynaptic responses
Neurotrophic factors Neurotrophic factors are released mainly by non-
neuronal cells and act on tyrosine kinase-linkedreceptors that regulate gene expression and
control neuronal growth and phenotypiccharacteristics
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Speed & receptors
Fast neurotransmitters (e.g.glutamate, GABA) operate throughligand-gated ion channels
Slow neurotransmitters andneuromodulators (e.g. dopamine,
neuropeptides, prostanoids) operatemainly through G-protein-coupledreceptors.
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Mediator typea Examples Targets Main functionalrole
Conventional small-
molecule mediatorsGlutamate, GABA,
acetylcholine,dopamine
, 5-hydroxytryptamine,etc.
Ligand-gated ion
channels G-protein-
coupled receptorsFast synaptic
neurotransmission
Neuromodulation
Neuropeptides Substance P,neuropeptide Y,
corticotrophin-releasingfactor, etc.
G-protein-coupled
receptorsNeuromodulation
Lipid mediators Prostaglandins,endocannabinoids
G-protein-coupled
receptorsNeuromodulation
Nitric oxide - Guanylate cyclase NeuromodulationNeurotrophins,
cytokines Nerve growth factor,brain-derivedneurotrophic factor,
interleukin-1
Kinase-linked receptors Neuronal growth,survival and functional
plasticitySteroids Androgens, oestrogens Nuclear receptors (also
membrane receptors)Functional plasticity
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GLUTAMATE
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Glutamate Roles
Increasing glutamate increases thefiring rate of a population of neurons
Excitability
Role in Cellular Memory
Pain Perception
Potentiation
Amplification
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Glutamate
Widely & fairly uniformly distributed
Made from glucose via Kreb cycle
Interconnection between
Excitatory & Inhibitory amino acidsmakes it difficult to study the
functional role of individual ones.
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Glutamate & GABA interlinked
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Glutamate receptors
Four main subtypes of EAA receptorscan be distinguished,
NMDA - ionotropic
AMPA - ionotropic
Kainate - ionotropic
Metabotropic - G-protein
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Dual Role of NMDA
NMDA receptors mediate slowerexcitatory responses and, throughtheir effect in controlling Ca2+ entry,
play a more complex role incontrolling synaptic plasticity (e.g.
long-term potentiation).
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NMDA receptors
Highly permeable to Ca2+, as well asto other cations Na+
Activation of NMDA receptors
Ca2+ entry. Blocked by Mg2+
Activation requires glycine &
glutamate Selective NMDA blocking agents
Ketamine & Phencyclidine (PCP-angel
dust) both dissociative anaesthetic
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Main sites of drug action onNMDA and GABAA receptor
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NMDA & Calcium
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Function of Glutamatereceptors NMDA Slow component to excitatory
synaptic potential
AMPA mediate fast excitatory
synaptic transmission in CNS, occursin astrocytes
Kainate presynaptic role
Metabotropic pre & postassociated with modulation
Presynaptic inhibit calcium channels
Postsynaptic inhibit potassium channels
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Glutamate
Chronic Pain
Mood Lability
Bipolar disease
Paroxysmal symptoms
Neurodegeneration
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Synaptic plasticity
Synaptic plasticityis a general term todescribe long-term changes in synapticconnectivity and efficacy, either
following physiological alterations inneuronal activity (as in learning andmemory), or resulting from pathological
disturbances (as in epilepsy, chronicpain or drug dependence).
NMDA antagonists prevent LTP
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GABA
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GABA
GABA functions as an inhibitorytransmitter in many different CNSpathways.
About 20% of CNS neurons areGABAergic; most are shortinterneurons, but long GABAergic
tracts run to the cerebellum andstriatum.
GABA serves as a transmitter at about
30% of all the synapses in the CNS.
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GABA Receptors
GABA acts on two distinct types ofreceptor
GABAA receptor - ligand-gated ion
channel located postsynaptically mediate fast
postsynaptic inhibition - Chloride
GABAB - G-protein-coupled receptor located pre- and postsynaptically
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Main sites of drug action onNMDA and GABAA receptor
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GABA receptors
GABAA receptors are the target forseveral important centrally actingdrugs,
Benzodiazepines, Barbiturates
Neurosteroids
General anaesthetics GABAB receptor
Baclofen selective agonist - used to treatspasticity and related motor disorders
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GABAB receptor
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GABA at the synapse
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Monoamine Transmitters
Noradrenaline (Norepineprine)
Dopamine
5 HT (Serotonin)
Acetylcholine
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NORADRENALINE
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Noradrenaline Synthesis
The basic processes responsible for thesynthesis, storage, release and
reuptake of noradrenaline are the same
in the brain as in the periphery and thesame types of adrenoceptor are also
found in pre- and postsynaptic locations
in the brain.
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Noradrenaline Function
The actions of noradrenaline are mainlyinhibitory (-receptors), but some areexcitatory (- or -receptors).
Noradrenergic transmission functions in the 'arousal' system, controlling wakefulness
and alertness
blood pressure regulation
control of mood (functional deficiencycontributing to depression).
NA dampen extraneous informationdrive a single experience and to ignore
distractions
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Noradrenaline excess
NA Sympathetic nervous system ofbrain
ADD, ADHD
ADD with comorbid anxiety Anxiety PTSD
Panic attacks
Depression
Sleep disturbances
Mediating survival mechanisms
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Copper &Ascorbic
Acid
Whatcofactors thatdriveDopamine toNoradrenaline
?
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Noradrenaline Pathway
The cell bodies of noradrenergicneurons occur in small clusters in thepons and medulla, and they send
extensively branching axons to manyother parts of the brain and spinal cord
The most prominent cluster is
the locus coeruleus (LC), located inthe pons.
descending control of pain pathways
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Noradrenergic Drugs
Psychotropic drugs that act partly ormainly on noradrenergic transmission inthe CNS include
Antidepressants Cocaine
Amphetamine.
Antihypertensive drugs clonidine &methyldopa
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DOPAMINE
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Dopamine & Brain Function
The brain is designed to orientate itselfto experience of high emotional valence
Meaning of event
Relevance Emotional significance
Pain and pleasure
Motivation
Cerebral microcirculation
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Dopamine Significance
Dopamine is particularly important inrelation to neuropharmacology;
Parkinson's disease
Schizophrenia hyperdopaminergic state Attention deficit disorder
Substance abuse
Endocrine disorders Fatigue, concentration difficulty, low
motivation (anhedonia)
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Dopamine Synthesis
Dopaminergicneurons lackdopamine -hydroxylase,and thus do notproducenoradrenaline.
Tyrosinehydroxylaseneeds iron ascofactor
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Dopamine Metabolism
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Dopamine Distribution
Distribution of dopamine in the brain ismore restricted than that ofnoradrenaline
Dopamine is most abundant inthe corpus striatum, a part of the
extrapyramidal motor systemconcerned with the coordination ofmovement
D i P th &
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Dopamine Pathways &Function Nigrostriatal pathway - 75% of the
dopamine in brain
Cell bodies in the substantia nigrawhose
axons terminate in the corpus striatum. Motor Control
Parkinsons Disease dopaminedeficiency here.
D i P th &
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Dopamine Pathways &Function
Mesolimbic/mesocortical pathways Cell bodies in midbrain and whose fibres
project to parts of the limbic system,
especially the nucleus accumbensandthe amygdaloid nucleusand to the frontalcortex.
Focus and orient frontal lobes to pay
attention Emotion and drug-induced reward systems
Mesocorticol dopamine deficiency - ADHD
Mesolimbic dopamine deficiency -
D i P th &
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Dopamine Pathways &Function Tuberohypophyseal system
Group of short neurons running from theventral hypothalamus to the median
eminence and pituitary gland
Regulate secretions of pituitary gland
Prolactin release (inhibited)
Growth hormone release (stimulated)
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Dopamine Pathway
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Dopamine Receptors
There are five dopamine receptorsubtypes.
Dopamine receptors.pdf
D1 and D5 receptors are linked tostimulation of adenylyl cyclase excitatoryfrontal lobe
D2, D3 and D4 receptors are linked to
inhibition of adenylyl cyclase - inhibitorysubcortical areas
Most known functions of dopamine
mediated mainly by receptors of the-
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Dopamine at the Synapse
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Dopamine Drugs
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Vomiting
Dopaminergic neurons have a role in theproduction of nausea and vomiting.
Nearly all dopamine receptor agonists (e.g.bromocriptine) and other drugs that increase
dopamine release in the brain (e.g. levodopa)cause nausea and vomiting as side effects,
Dopamine antagonists (e.g. phenothiazines,metoclopramide) have antiemetic activity.
D2 receptors occur in the area of the medulla(chemoreceptor trigger zone) associated with theinitiation of vomiting and are assumed to mediatethis effect.
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Analogy
Dopamine is caveman hanging out athis woods, he has to sit quietly, payattention to where the prey is, at the
right moment kill it activating arousalneurotransmitter
Serotonin is dragging the meat back to
cave, chewing on it by the fire, eating,then go to sleep homeostasisneurotransmitter
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SEROTONIN
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Serotonin (5-HT)
Lysergic acid diethylamide (LSD), adrug known to be a powerful hallucinogenacted as a 5-HT antagonist on peripheral
tissues, and suggested that its centraleffects might also be related to this action.
5HT2A
5-HT is mainly found in 99% in gut, but1%
in brain important.
Selective serotonin reuptake inhibitorsconstitute an important group of
antidepressant drugs.
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5-HT Synthesis
5-HT synthesisresemblesnoradrenaline.
Except precursor isTryptophan notTyrosine
Availability oftryptophan is themain factorregulatingsynthesis
5 Hydroxytryptamine
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5-Hydroxytryptaminepathways
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Serotonin Pathways
5-HT neurons are concentrated in themidline raphe nuclei in the pons andmedulla,
Projecting diffusely to the cortex
Limbic system
Hypothalamus
Spinal cord
Similar to the noradrenergicprojections.
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Serotonin at the receptor
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5-HT Receptors9 main receptors
5-HT1A
5-HT1B 5-HT1D 5-HT2 5-HT3 5-HT4
5-HT6 5-HT7
5-HT Receptors.pdf
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5-HT Functions
Functions associated with 5-HTpathways mainly vegetative functions
Social engagement
Mood and emotion Appetite
Sleep/wakefulness
Control of sensory pathways, includingnociception
Body temperature control
Vomiting
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Serotonin imbalance
Depression Anxiety
Obsessions and Compulsions
Pain Sensitivity
Aggression
Sleep Disorders
Tryptophan Hydroxylase
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Tryptophan HydroxylaseModulation
Inhibited By
Nitric oxide
L Dopa
Polychlorinatedbiphenyls
Nicotine
Activated By
Oxygen Folic acid
Sulfhydryl
groups SSRIs
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Natural Serotonin Agonists
5 HTP Folic acid( MTHF crosses BBB)
DHEA
Vitamin D
St Johns Wort (Hypericum chinense)
Physical activity
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5-HT receptor selective drugs
Serotonin reuptake inhibitors (SSRIs)-fluoxetine, used as antidepressants
5-HT1D receptor agonists, -
sumatriptan - treat migraine 5-HT1A receptor agonist used in
treating anxiety - buspirone &
vitamin D 5-HT3 receptor antagonists, -
ondansetron - antiemetic agents
Antipsychotic drugs - clozapine
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ACETYLCHOLINE
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Acetylcholine Synthesis
Synthesis, storage and release ofacetylcholine (ACh) in the central
nervous system (CNS) areessentially the same as in the
periphery
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Acetylcholine pathways
ACh is widely distributed in the CNS,important pathways being:
Magnocellular forebrain nuclei which
send a diffuse projection DegenerationAlzheimers Dementia
Septohippocampal projection
Short interneurons in the striatum and
nucleus accumbens.
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Acetylcholine pathways
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Acetylcholine Receptors
Acetylcholine has mainly excitatoryeffects
Nicotinic (ionotropic)
Muscarinic (G-protein-coupled somemuscarinic ACh receptors (mAChRs) areinhibitory.
The mAChRs in the brain arepredominantly of the M1 class
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Acetylcholine at the Synapse
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Acetylcholine Function
Muscarinic receptors appear tomediate the main behavioural effectsassociated with ACh,
Arousal Learning
Short-term memory.
Muscarinic antagonists (e.g.scopolamine) cause amnesia.
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Acetylcholine Drugs
Acetylcholinesterase Inhibitor Tacrine Donepezil Galantamine
Rivastigmine
Memantine, an NMDA receptorantagonist.
Huperzine(Huperzia serrata) chineseclub moss - Reversible and selective ACHeinhibitor.
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References
Rang et al (2007) Rang & DalesPharmacology 6th Ed.
Jay Lombard DO Neurotransmitters
& Behaviour