Post on 20-Feb-2018
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Neurotransmitters &Neuromodulators
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oncepts you s oualready know before this
lecture Cell membrane ion channels Resting membrane potential
Local potentialTemporal summationSpatial summation
Action potential EPSP IPSP
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Types of Synapses in theCNS
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Presynaptic Inhibitionand Facilitation
Axoaxonic synapses mediatepresynaptic inhibition and facilitation,eg present in the spinal cord to
regulate the propagation ofinformation to the brain
Interneurons regulate the ability of thepresynaptic neurons to releaseneurotransmitters by changing theamount of Ca!!in"ux to thepresynaptic neurons
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http://www.ncbi.nlm.nih.gov/books/NBK11164/
Electrical vs ChemicalSynapse
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Type Electrical Chemical
Length ofsynapticcleft
#$ nm %&'(& nm
Cytoplasmi
c continuity
)es *o
Structure +ap unction Presynaptic-esiclesPostsynapticreceptors
Agents oftransmission
Ion current.electrical/
*eurotransmitters .chemical/
Synapticdelay 0irtuallyabsent 1 2'$ ms
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Dobrunz,
!""!
Chemical Synapse
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Synaptic Communication
Total 6 of action potentials reaching thepresynaptic terminal directly in"uencesthe amount of neurotransmitter released
7excitatory stimuli to the presynapticneuron cause increased 6 actionpotentials reaching the presynapticterminal
7duration of excitatory stimuli to thepresynaptic neuron cause a longerseries of action potentials reaching thepresynaptic terminal
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NE!"#T"$NS%ITTE"S$N NE!"#%#!'$T#"S
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(hat is aNeurotransmitter)
It is synthesi8ed in the neuron It is present in the presynaptic terminal It is released in amounts su9cient to
exert an action on the postsynapticneuron or e:ector organ
It is remo-ed from the synaptic cleft bya speci;c mechanism
Synaptic -esicle cyclinghttp
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(hat is aNeurotransmitter)
>hen administered ?exogenously@ .egdrugs/ in reasonable concentration, itmimics the action of the endogenously
released neurotransmitter exactly Itacti-ates the same ion channels orsecond messenger system in thepostsynaptic cell
Some de;ne neurotransmitters toinclude neuromodulators that act aayfrom the synaptic cleft .4lumefeld, %&2&/
Schart8,
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(hat is aNeuromodulator)
Act at a distance aay from the synapse Bodulate acti-ity of many neurons Released into extracellular "uid The same chemical substance can act
either as a neurotransmitter orneuromodulator
E:ects last minutes to days
*eurotransmitters and neuromodulatorscan be released simultaneously
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Functions ofNeurotransmitters
Bediate communication beteen neuronsor the end'organs through fast excitatory.EPSP/ or inhibitory .IPSI/ postsynapticpotentials .2 ms/
3irectly opening ligand'gated ionchannels on postsynaptic membrane
Slo'acting neuromodulation, occurringo-er 2&&ms to minutes
Indirect opening ion channels oracti-ation the cellular signaling cascades
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Neurotransmitter"eceptors
Receptors are often named accordingto the neurotransmitters to hich theybind, eg +A4AA, +A4A4, $'DTreceptors
The same neurotransmitter may bindto se-eral types of receptors, egSerotonin
The e:ect of neurotransmitters on apostsynaptic neuron is determined bythe type of receptors present on itsmembrane, eg Ach, *orepinephrine
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%echanisms+ irect
$ctivation of IonChannels
*eurotransmittersbind to receptors thatare part of the ligand'gated ion channels
and directly open theion channels
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%echanisms+ Indirect
$ctivation of IonChannels
*eurotransmittersbind to receptors thatare separate from theion channels, andindirectly open the ionchannels by acti-atingthe +'protein This
process in-ol-eschanges in themetabolism of the cell
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*na ransm ss on%echanisms+ $ctivatin*
Intracellular Si*nalin*Acti-ation of the +'protein second'
messenger systemcan trigger theintracellular signalingcascade This process
has long lastinge:ects on regulatinggenes expression andneuronal groth
4yrne, 2F
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Termination of SynapticTransmission
Remo-ing neurotransmitters3i:usion< remo-e a fraction onlyEn8ymatic degradation< eg
acetylcholinesterase
ReuptaGe< most common, eg serotonin 3esensiti8ing receptors by
Receptor internali8ation< folding thepostsynaptic membrane containing thereceptors into the cell
Receptor inacti-ation
C
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CommonNeurotransmitters and
Neuromodulators Amino AcidH+A4A
H+lutamate.+lu/H+lycine .+ly/
CholinergicHAcetycholine
.ACh/
AmineH3opamine .3A/HSerotonin .$'
DT/H*orepinephrin
e .*E/
PeptideHSubstance PHEndorphins
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$mino $cid+ ,$-$
ast'acting BAJKR inhibitoryneurotransmitter found in the entire C*S,eg inhibitory interneurons in spinal cord
Pre-ents excessi-e neural acti-ity4arbiturates mimics the action of +A4A
and are used for sedation, asanticon-ulsants
4aclofen, a muscle relaxant to controlmuscle spasticity, increases presynapticrelease of +A4A
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$mino $cid+ ,lutamate.,lu/
ast'acting BAJKR excitatoryneurotransmitter found in the entire C*S
In-ol-ed in learning and memory +lutamate is present in a ide -ariety of
foods, eg BS+K-eracti-ity of glutamate may cause
sei8ures
Excitotoxicity
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,lutamate "eceptors
ABPA< ligand gated receptor *B3A< ligand' and -oltage'gated receptor
Postsynaptic neuron must depolari8e
hen the +lu binds to the *B3Areceptor in order to open the gate
Prolonged opening of ion channelsresulting in long'term potentiation .LTP/
Betabotropic glutamate receptor< indirectacti-ation by +'protein pathay
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$cetylcholine .$Ch/
%$0#"neurotransmitters in PNS1 $NSast'acting e:ect< act at neuromuscularunction, eg *icotinic receptors
Slo'acting e:ect< regulate DR, A*Sfunction, eg Buscarinic receptors
Primary as a neuromodulator in C*S
Controls locomotion, arousal
acilitate attention, memory, learning
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Nicotinic %uscarinic
4ind nicotine 4ind muscarineLinGed to ionchannels
LiGed to %ndmessenger systemthrough + protein
ast and briefresponse
Slo and prolongedresponse
Located at
neuromuscularunctions,autonomicganglia, and some
C*S
ound on myocardial
muscle, certainsmooth muscle, insome C*S regions
Choliner*i
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Choliner*ic
Pro2ection
Systems
4lumefeld,
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$cetylcholine
Applying electrical stimulation topontomesencephalic region of thebrainstem elicits coordinated locomotormo-ements
3rugs that blocG the cholinergictransmission in the brain causes deliriumand memory de;cits3egeneration of cholinergic neurons in the
basal forebrain may be associated ithmemory decline in $l3heimer4s disease
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%yasthenia ,ravis .%,/
ACh receptors on muscle membranesare destroyed >eaGness becomesmore se-ere ith repetiti-e use of amuscle
Rx< Anticholinesterase inhibits thecholinesterase from breaGing donACh
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%yasthenia ,ravis .%,/
&'(uc'( )*+ $mplitu('sov'r r'p'titiv' muscl'contr$ctions.
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$mines+ opamine .$/
Produced in substantia nigra of basalganglia and -entral tegmentum
Primarily an inhibitory e:ect in C*S
All 3A receptors are %ndmessengersystems to suppress the acti-ity ofCa!! channels
A:ects motor acti-ity,moti-ation=reard beha-ior, andcognition
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opamine Pro2ectin*System
B+ imbic -r'ront$l
*ov'm'nt &'w$r( orking *'mor0
((iction tt'ntion
euro o* c on t ons
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euro o* c on t ons$ssociated with
opamine .$/ParGinsonMs 3isease Case< N3A in basalganglia3epression=Cogniti-e< N3A in forebrain
3rug addiction< cocaine andamphetamines interfere ith 3AreuptaGe into the presynaptic neurons,
alloing 3A to acti-ate receptorsrepetiti-elySchi8ophrenia< too much 3A
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$mines+ Serotonin .567T/
Produced in raphe nuclei and +I tract Serotonin regulates sleep'aGe cycle,
cognition, perception of pain, breathing,
temperature, mo-ements, and mood Serotonin is associated ith depression,anxiety, obsessi-e'compulsi-e disorder,aggressi-e beha-ior, certain eating
disorders .release serotonin Nappetite/ Serotonergic neurons N;ring during sleep
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$mines+ Serotonin .567T/
Serotonin is ?happiness hormone@Serotonin Nperception of pain Lole-els of serotonin are associated ith
depressionPro8ac .antidepressant/ is a selecti-e
inhibitor of serotonin reuptaGe .soserotonin stays in the synaptic cleft
longer to bind ith receptors/SI3S may be associated ith defected
serotonergic neurons
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Norepinephrine .NE/
Regulate functions of A*S, thalamus,and hypothalamus
Bodulate attention, sleep'aGe cycle
*oradrenergic neurons N;ring in sleepAttention'de;cit disorders if often
treated ith medications that enhance*E transmission
7le-el of *E is associated ith -igilance,7alertness, and ?;ght'or'"ight@ response
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Norepinephrine .NE/
*oradrenergic neurons in-ol-e insympathetic functions such as bloodpressure control
Similar to Serotonin, *E alsoNperception of pain in the C*S, andplays a role in many psychiatricsyndrome
N*E can cause depression7*E can cause anxiety .panic attacG/
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SerotoninPro2ection
System
Noradrener*ic
Pro2ectin*Systems
Blum''l(, !"1"
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7istamine
ound mainly in the hypothalamus ound mostly outside the ner-ous
system in mast cells that mediate
immune responses and allergicreactions Role of histamine in the brain
Baintain the alert state
Excitatory e:ects on thalamusAntihistamine medications can cause
drosiness by blocGing C*S histaminereceptors
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Peptides+ Substance P
Released from the terminals of somesensory ner-e ;bers
*eurotransmitter function in thenocicepti-e pathaystimulates free ner-e endings at the
site of inury and transmit painsignals from the periphery to the C*S
*euromodulator function in the chronicpain syndrome increase pain perception
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Peripheralsensiti8ationfolloing celldamage Painsignals cause the
free ner-e endingsto releasesubstance P$'DT outside the
ner-ous systemstimulates thenocicepti-e freener-e endingsSP'substance PDauser, %&2&
ept es+ n o*enous
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ept es+ n o*enous#pioids
.endorphin1 enkephalin1dynorphin/
4odyMs natural painGillers
Inhibit C*S neuronsin-ol-ed in theperception of pain
Exercise increasesendogenous opioids
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Nitric #8ide .N#/
An free radical, highly reacti-e,di:usible gas molecule ithneuromodulator e:ects
*K is important in the regulation ofcerebral blood "o, neurotransmission,long'term potentiation, excitotoxicity.ie neuronal death/
*K cause blood -essels to dilate *K in excess is toxic to cells