Neurotransmitters

Atif H. Khirelsied. Ph.D. H Khirelsied Ph D Department of Biochemistry D f Bi h i Faculty of Medicine International University of Africa.

Neurotransmitters
Neurotransmittersarechemicalsmessengersthatrelay, amplify andmodulate signalsbetweenaneuronand anothercell.

Neurotransmitters enablethetransmissionofimpulses acrossthesynapse. across the synapse

4/3/2012

Dr.AtifHassanKhirelsied

Neurotransmitters

Theclassesofneurotransmitters The classes of neurotransmitters

Basedontheirchemicalnature,therearethree majortypes:

1. Aminoacidsandamines. 2. Neuropeptides. 3. Gases.

4/3/2012

Dr.AtifHassanKhirelsied

Theamines The amines

The amines are divided into two sub groups: Theaminesaredividedintotwosubgroups: Catecholamines:
Dopamine Norepinephrine Epinephrine

Indolamines
Serotonin. Melatonin

Thecatecholamines The catecholamines

Dopamine (dihydroxyphenylalanine (acronym Dopamine(dihydroxyphenylalanine (acronym DOPA).

Norepinephrine E i Epinephrine hi

Catecholaminessynthesis

The dopamine
dihydroxyphenylalanine (acronym DOPA) (acronymDOPA). Producedinseveralareasofthebrain,includingthe substantia nigra andtheventraltegmental area. Has five types of receptors (D1, D2,, D5). Hasfivetypesofreceptors(D ,D ,,D I t Intravenousinfusionproducesincreasedheartrate i f i d i dh t t andbloodpressure..

TherearefivedifferentDAreceptorsubtypesthatbelongtotwo families(D D ). families (D1,D2)

Dopamine
Inactivationanddegradation Therearetwomajordegradationpathwaysfordopamine. Inthebrain(striatum,basalganglia),dopamineis removedbydopaminetransporter(DAT1),thendegraded bymonoamineoxidase (MAOAandMAOB)into3,4 dihydroxyphenylaceticacid. Intheprefrontalcortex,itisremovedbynorepinephrine transporter(NET),thendegradedbycatecholOmethyl transferase (COMT)into3methoxytyramine.

Thedegradationofdopamine

Thedegradationofcatecholamines

Dopamine
Severaldiseasesofthenervoussystemareassociated Several diseases of the nervous system are associated withthedopaminesystem. Parkinson'sdisease,iscausedbylossof dopamine secretingneuronsinthesubstantia dopaminesecreting neurons in the substantia nigra. Schizophrenia involveselevatedlevelsof dopamineactivityinthemesolimbic pathway dopamine activity in the mesolimbic pathway anddecreasedlevelsofdopamineinthe p f prefrontalcortex.

TheroleofDAinParkinson s The role of DA in Parkinson's

Symptoms: S t Motorandcognitiveimpairment. T Tremors Rigidity Cause: D DegenerationofDAneuronsinthesubstantia nigra. ti f DA i th b t ti i Treatment: T t t Ldopa,DAcannotcrosstheBBB.

Parkinson'sdisease,iscausedbylossofdopaminesecreting neuronsinthesubstantia neurons in the substantia nigra.

Norepinephrine

Adrenergicreceptorsubtypes Adrenergic receptor subtypes

Allaremetabotropic receptors. Therearetwobasictypes: Manydrugsusedtotreatnonpsychiatricconditions y g py actonadrenergicreceptorsinthePNS.

NEandEPIintheCNS NE and EPI in the CNS

Th Theprimarylocationofnoradrenergicneuronsinthe i l i f d i i h CNSisthelocuscoerulus. NEisinvolvedin: Hunger Sex Fear Anxiety y Pain Sleep and arousal Sleepandarousal

Examplesofdrugsaffectingadrenergicsystem
Drug
Phenelzine (antidepressant) methylparatyrosine(AMPT) (Pheochromocytoma) Reserpine (antipsychoticand antihypertensive) Amphetamine ( A h t i (psychostimulant) h ti l t) Cocaine (psychostimulant) (p y ) Propranolol (hypertensive)

Action
Increasecatecholaminesby inhibitingMAO Depletescatecholaminesby inhibitingtyrosinehydroxylase Depletescatecholaminesby inhibitingvesicular uptake Releasecatecholamines R l t h l i Inhibitscatecholaminesreuptake p Blocksreceptors

Indolamines

Serotonin
Theaminoacidtryptophan isaprecursorof neurotransmitterserotonin whichinturnisthe t itt t i hi h i t i th p precursorofhormonemelatonin..

Biosynthesisofserotonin

SSRI:Selectiveserotoninreuptake inhibitors

Thedegradationofserotonin

Featuresofthe5HTsynapse
5HTreleasingneuronssharemanyofthesamefeaturesas Dopamineandnorepinephrine releasingneurons. Reuptakeoccursviathe5HTtransporter. SSRIs block this transporter SSRIsblockthistransporter BreakdownoccursviaMAO,butnotCOMT. Thereareatleast15different5HTreceptorsubtypes.

Doeseatingtryptophanincrease5HTlevels?

Largedosesoftryptophandoincrease5HTlevelsin animals(Trp competeswithotheraminoacidsfor animals (Trp competes with other amino acids for uptakeintothebrain). HighCHOmealsreleaseinsulinwhichstoresamino acids,butnottrp,thusincreasingtheamountoftrp id b h i i h f availableby14%.

Theaminoacids
Excitatoryaminoacids:createEPSPS
Glutamate MainexcitatoryNTinCNS A Aspartate t t

Inhibitoryaminoacids:createIPSPS hb
Gammaaminobutyric acids(GABA) MaininhibitoryNTinCNS hb Gl i Glycine Normallyinhibitsmotorneuronactivityinspinalcord

Glutamatereceptors. Glutamate receptors

Therearetwobroadcategoriesofglutamatereceptors: f p p g g 1. Ionotropic receptorsareligand gatedionchannels. 2. Metabotropic areGproteincoupledreceptors.

Theyareresponsibleforexcitationofneuralcells. They are responsible for excitation of neural cells.

Glutamatereceptors p
Therearetwotypesofionotropicglutamatereceptors There are two types of ionotropic glutamate receptors inthebrain:
1. AMPA: standardionotropicEPSPcreatingreceptor, involvedin:locomotor activityandcoordination. involved in: locomotor activity and coordination 2. NMDA:special.NormallyblockedbyMg+2 AMPA=(amino3hydroxyl5methyl4isoxazolepropionate)isa
compoundthatisaspecificagonistfortheAMPAreceptor. compound that is a specific agonist for the AMPA receptor

NMDA =(NmethylDasparticacid)isanaminoacidderivativeactingasa ( y p ) g
specificagonistattheNMDAreceptor.

Glutamatereceptors

GABA:themajorinhibitorintheCNS GABA: the major inhibitor in the CNS

GABAissynthesizedfromGlutamateinonestep.

GABA
GABAisremovedfromthesynapsebytransporter proteinslocatedinglial cells. Approximately 40% of nerve terminals in the cortex, Approximately40%ofnerveterminalsinthecortex, hippocampusandsubstantia nigrauseGABA. TherearetwoGABAreceptors:
1. 1 GABAA:Ionotropic I i 2. GABAB:Metabotropic

TheGABA The GABAAReceptor

Thereceptorisamultimeric receptorthatconsistsoffive subunitsarrangedaroundacentralpore. ActivationofGABAA receptorsallowsCl toflow(the p ( chlorideshunt). Thishyperpolarize therestingpotential,andmakeit difficultforexcitatoryNTstodepolarizetheneuron. y p

TheGABAAReceptor

TheGABA The GABAAReceptor

InadditiontotheGABAbindingsitethereceptorhassites forexogenousligands. Benzodiazepines(BDZs) Barbiturates Ethanol TheseligandsincreasedtheeffectofGABAandtypically haveanxiolytic,anticonvulsant,amnesic,sedative, y , , , , hypnotic,euphorianteffects.

TheGABA The GABABReceptor

Theyaremetabotropictransmembranereceptorsfor linkedtoGproteinsandK+channels. Open K+ channels and hyperpolarize the resting OpenK channelsandhyperpolarize theresting potential PreventsNa+ channelsopeningandactionpotentials fromfiring. from firing

Neuropeptides

Neuropeptides: p p
Neuropeptidesaresmallproteins. p p p LargerthanotherNTs. Madeincellbody(soma). Packagedinsecretorygranules. Packaged in secretory granules CanbereleasedfromsamesynapseasotherNTs. Donotactuponionchannels

Solublegases

Solublegases Soluble gases

Producedincytoplasmbyenzymes. Diffusefreelyacrossmembranetoneighboringneurons.

Nitrousoxide(NO)
Regulatesvasculartone. Involvedinlearningandmemory.

Carbonmonoxide(CO)
Regulatesvasculartone. g Regulatesperistalsis.