Overview CNS Chemical Transmission

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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-
http://dopamine%20receptors.pdf/http://dopamine%20receptors.pdf/


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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
http://5-ht%20receptors.pdf/http://5-ht%20receptors.pdf/http://5-ht%20receptors.pdf/http://5-ht%20receptors.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

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