Neuro Transmitator

7/21/2019 Neuro Transmitator

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Neurotransmitters

Anant Kumar RathiFinal Year Resident, Psychiatry

Medical College, Kota (Raj.)



Ojecti!es

"# Outline the criteria that need to e mete$ore a molecule can e classi%ed as&neurotransmitter'

# denti$y the major neurotransmitter ty*es

+# Mechanism o$ action o$ im*ortantneurotransmitters

# denti$y some clinical disorders that canarise as a result o$ disru*tion o$



Otto -oei/s 01*eriment #"2"



3his is a 405RO4.

6endrites are ranching%ers that recei!ein$ormation $rom otherneurons

7oma is the cell odyo$ a neuron. tcontains a nucleus,riosomes,

mitochondria, andother structures. 3hisis here much o$ themetaolic or8 ta8es*lace

A1on is a thin%er herein$ormation issent $rom the

neuron to otherneurons

Soma

Presynaptic terminals

Presyna*ticterminals arethe *oint herethe a1onreleaseschemicals

Dendrit

es

Axon



Pre-synaptic Neuron

Post-synaptic Neuro

Neurotransmitters are sentthrough theaxon to pre-synapticterminals, andthen toanother

neuron



Summary

4eurotransmitter comes $rom soma

t tra!els through the a1on

From the *re#syna*tic terminal it ista8en through the syna*se to thene1t neuron

Re#u*ta8e sometimes occurs



405RO3RA47M330R7

9

Chemical transducersreleasedBy electrical impulseInto the synaptic cleftFrom pre-synaptic

memraneBy synaptic !esicles"

Di#use to the post-

synaptic memrane$eact and acti!ate thereceptors present%eading to initiation ofne& electrical signals"



:



4eurotransmitter rece*tors

• Once released, the neurotransmitter molecules di;use acrossthe syna*tic cle$t

• <hen they &arri!e' at the *ostsyna*tic memrane, they ind toneurotransmitter rece*tors

• 3o main classes o$ rece*tors= – -igand#gated ion channels

• transmitter molecules ind on the outside, cause the channel to o*en andecome *ermeale to either sodium, *otassium or chloride

–>#*rotein#cou*led rece*tors• >#*rotein#cou*led rece*tors ha!e sloer, longer#lasting and di!erse

*ostsyna*tic e;ects. 3hey can ha!e e;ects that change an entire cell/smetaolism

• or an en?yme that acti!ates an internal metaolic change inside the cell• acti!ate cAMP• acti!ate cellular genes= $orms more rece*tor *roteins• acti!ate *rotein 8inase= decrease the numer o$ *roteins



01citatory neurotransmitters=



nhiitory neurotransmitters=



4eurotransmitters in rainA)IN*S

Dopamine

SerotoninNor-

epinephrine*pinephrine

Acetylcholine)elatonin+istamine

A)IN ACIDSlutamic acid

ABAlycine

Aspartic acid

PIIDSP*P.ID*S

Dynorphins*ndorphin

*n/ephaline

)ISC*%%AN*

0SP*P.ID*S

Brady/ininNeuropeptid

e 1 Neurotensin

Bomesin

PI.0.$1

P*P.ID*SAC.++.S+

xytocin2asopressin

ProlactinAlpha )S+

CI$C0%A.IN+$)N*S

AngiotensinCalcitoninlucagon

Insulin*strogen.hyroid

hormonesCortisol

+1P.+A%A)

IC $*%*ASIN+$)N*SC$+

n$+%+$+.$+

+$+Somatostatin

AS*S

NCN*0$3ININ

SSustance p

%IPID N.

AnandamideP0$IN*S



4euromodulators

• 4eurotransmitters transmit an im*ulse $romone neuron to another

• 4euromodulator modulate regions or circuits o$

the rain

• 3hey a;ect a grou* o$ neurons, causing amodulation o$ that grou*

• 4euromodulators alter neuronal acti!ity yam*li$ying or dam*ening syna*tic acti!ity – eg. do*amine, serotonin, acetylcholine, histamine,

glutamate



6o*amine # as 43 y Ar!id Carlsson"2@:

• 6OPA is con!erted sora*idly into 6o*aminethat 6OPA le!els arenegligile in the rain

• Rate o$ synthesis isregulated y – Catecholamine acting as

inhiitor o$ 3

– A!ailaility o$ B

– Presyna*tic 6A rece*tors

– Amount o$ acti!ity innigrostriatal *athay



Metaolism

• n rats 6OPAC majormetaolite

• n *rimates andhuman DA majormetaolite

• Accumulation o$ DAin rain or C7F usedas inde1 o$ $unction o$do*aminergic neurons



6o*aminergic *athays

da*ted $rom noue and 4a8ata. Jpn J Pharmacol. EE":G=+9G.

4igrostriatal*athay

(*art o$ 0P system)

3ueroin$undiular *athay(inhiits *rolactin release)

Mesocortical*athay

Mesolimic*athay



6o*aminergic Pathays

":Moore et al. "29:



7igni%cance o$ 6o*aminergicPathays

• Mesolimic Pathay – Associated ith *leasure, reard and goal directed

eha!ior

• Mesocortical Pathay – Associated ith moti!ational and emotional res*onses

• 4igrostriatal Pathay – n!ol!ed in coordination o$ mo!ement (*art o$ asal

ganglia motor loo*)

• 3ueroin$undiular Pathay – Regulates secretion o$ *rolactin y *ituitary gland and

in!ol!ed in maternal eha!ior

"2



6o*amine hy*othesis o$schi?o*hrenia



Par8inson/s 6isease

• 7ustantial loss o$ 6o*aminein the striatum (9E :EH)

• -oss o$ do*amine neurons inother systems also(mesolimic, mesocorticaland hy*othalamic systems)

• 3reatment strategy includesincreasing do*amine le!els

y administering -#6o*a,ner!e gra$ting ithdo*amine containing cellsand dee* rain stimulation

"



6o*amine and Addiction

• 3he do*aminergic *rojection to !entral striatum haso$ten een im*licated in the mechanisms $oraddiction

• ncreased loco motor acti!ity and stereoty*y causeddue to *sycho stimulant in!ol!e do*amine release instriatum

• Cocaine inds to 6A3 (at a di;erent site) *re!enting

the reu*ta8e o$ do*amine y the cells leading to anincreased e1tracellular le!els o$ do*amine

• Am*hetamine acts as a $alse sustrate and istrans*orted into the cyto*lasm and results in re!ersetrans*ort o$ do*amine $rom cyto*lasm to thee1tracellular s*ace



Nor-epinephrine



4ore*ine*hrine or 40• In the CNS, norepinephrine is used y neurons of

the locus coeruleus, a nucleus of the rainstem&ith complex modulator functions

• In the peripheral ner!ous system, norepinephrineis the transmitter of the sympathetic ner!oussystem

• In!ol!ed in sleep, &a/efulness, attention andfeeding eha!ior

• At least t&o /inds of N* receptors4 N* alpha andN* eta

• Indicated e#ects4

– primarily excitatory

– appears to modulate Fear56ight57ght system

• .oo much4 o!er arousal, mania



Remo!al o$ Catecholamines

• All three catecholamines areremo!ed y selecti!e reu*ta8e y

the *resyna*tic a1on terminals• 3hey are either reused ordegraded y monoamine o1idase(MAO)



7erotonin

7ecreted y the nuclei originating in the median

ra*he o$ the rain stem and terminate in dorsalhorn o$ the s*inal cord and hy*othalamus



N

C

N

C N+'

C+ C+

N+'

+

N

C N+'

+ +

.ryptophan 8-+ydroxytryptophan

8-+ydroxytryptamin

N

C C+

8-+ Indole

Acetaldehyde

8-+ydroxy IndoleAcetic Acid

.ryptophan hydroxylase

8-+ .ryptophan decaroxylase

) A ,

A l d e h

y d e

d e h y d r o g e n a s e

(Ratelimiting)

n diet. Acti!eC47 trans*ort



• *xcitatory 9 Inhiitory

• Control the mood o$ the *erson and im*ortantin slee*

• Also *resent in >3, *latelets I limic system

• Rece*tors= "A, "B, "6, A, C, +, , @, G, 9

• -o le!els are associated ith de*ression andother *sychiatric disorders

• May e in!ol!ed in migraine



Amine 4eurotransmitters



)any antidepressants are speci7c to this N.

SS$I:sBloc/ reupta/e of 8+. in the synapse



C + ,

% I N * $ - I

C

N * 0 $

, N

I t c a n e e x c i t

a t o r y o r

i n h i

i t o r y



Cholinergic rece*tors

• 3o 8inds o$ rece*tors – Nicotinic

• Nicotine stimulates• *xcitatory; found predominately on neuromuscular

<unctions

– )uscarinic• )uscarine =mushroom deri!ati!e> stimulates

• Both excitatory AND Inhiitory; found predominately inrain

• Indicated e#ects4 – excitation or inhiition of target organs – essential in mo!ement of muscles

– important in learning and memory



Ach Al?heimerJs disease



Cholinergic neurons ha!e interactions ithall three monoamine systems.

Agonist can *roduce lethargy, anergia and

*sychomotor retardation in normalsujects.

#can e1acerate sym*toms inde*ression

#can reduce sym*toms in mania.



M0-A3O44

• Melatonin is *roduced y the *ineal gland, asmall endocrine gland located in the centero$ the rain ut outside the loodrainarrier

• Regulates the slee*#a8e cycle *aracrinee;ect 7C4

• Antio1idant

• mmune system• Autism

• Par8insonJs disease



>-53AMA30



>ABA



• 6ecreased >ABA#A rece*tor indingin a *ositron emission tomogra*hy(P03) study o$ *atients ith *anic

disorder.• -o *lasma >ABA has een re*orted

in some de*ressed *atients and, in

$act, may e a use$ul trait mar8er $ormood disorders.

PA i ( )



PA a1is (hy*othalamo#*ituitary#adrenal a1is)

*le!ated +PA acti!ity is a hallmar8 o$ mammalian stress

res*onses and one o$ the clearest lin8s eteen de*ressionand iology o$ chronic stress.

@EH o$ de*ressed *atients ha!e ele!ated cortisol le!el

(resol!es ith treatment ### *ersistently increased le!el

indicate a high ris8 o$ rela*se )

CR le!els are also ele!ated in C7F o$ de*ressed *ts.

(Central CR rece*tor antagonists#*ossile antide*ressants)

0le!ated PA acti!ity in de*ression has een documented !ia6e1amethasone 7u**ression 3est.

4onsu**resion may im*licate a loss o$ inhiitory hi**ocam*alglucocorticoid rece*tors resulting in increased CR dri!e.



B i 6 i d 4 t hi F t



Brain 6eri!ed 4eurotro*hic Factor(B64F)

• Protein is coded y the B64F gene locatedon chromosome ""

• t is acti!e in the hi**ocam*us, corte1 and asal $orerainareas !ital to learning, memory, and higher thin8ing.

• B64F itsel$ is im*ortant $or long#term memory

• el* to su**ort the sur!i!al o$ e1isting neurons, andencourage the groth and di;erentiation o$ ne neuronsand syna*ses

• Darious studies ha!e shon *ossile lin8s eteen B64F

and conditions suchas de*ression, schi?o*hrenia, osessi!e#com*ulsi!edisorder, Al?heimerJs disease, untingtonJs disease, Rettsyndrome, and dementia as ell as anore1ianer!osa and ulimia ner!osa



B64F I 6e*ression

• 01*osure to stress and the stresshormone corticosterone has een shon to decreasethe e1*ression o$ B64F in rats

• $ e1*osure is *ersistent, this leads to an e!entual atro*hy

o$ the hi**ocam*us.• Atro*hy o$ the hi**ocam*us and other limic structureshas een shon to ta8e *lace in humans su;ering $romchronic de*ression

• 01citatory neurotransmitter glutamate,

!oluntary e1ercise, caloric restriction, intellectualstimulation, curcumin and !arious treatments $orde*ression antide*ressants and electrocon!ulsi!ethera*y and slee* de*ri!ation increase e1*ression o$ B64Fin the rain.



Al?heimer/s disease

• Post mortem analysis has shon loered le!els o$ B64F inthe rain tissues o$ *eo*le ith Al?heimerJs disease

• 4eurotro*hic $actors ha!e a *rotecti!e role against amyloideta to1icity

• A connection eteen de*ression and dementia has eensuggested to e mediated y B64F

• 6e*ression causes shrin8age o$ the hi**ocam*us. <henantide*ressants are administered, the le!els o$ B64F areraised to *rotect and increase the !olume o$ hi**ocam*aland other cells

• n Al?heimerJs, the hi**ocam*us is also damaged, loeringle!els o$ the neurotro*hic $actor

• Another *ossile lin8 eteen B64F and dementia isthrough %tness, since e1ercise can release B64F and*reser!e cognition in older *eo*le



• 6rug de*endency # Animals chronically e1*osedto drugs o$ ause sho increased le!els o$ B64Fin the !entral tegmental area (D3A) o$ the rain

• <hen B64F is injected directly into the D3A o$rats, the animals act as i$ they are de*endent ono*iates

• 0*ile*sy # le!els o$ oth B64F mR4A and B64F*rotein are 8non to e u*#regulated in e*ile*sy

• B64F modulates e1citatory and inhiitorysyna*tic transmission y inhiiting >ABAA#rece*tor#mediated *ost#syna*tic currents

>li l ll li 6 i d 4 t hi



>lial cell line 6eri!ed 4eurotro*hicFactor (>64F) $amily o$ ligands

• Four neurotro*hic $actors= – >lial cell line#deri!ed neurotro*hic $actor (>64F),

– 4eurturin (4R34),

– Artemin (AR34)

– Perse*hin (P7P4)

• Play a role in cell sur!i!al, neurite outgroth,cell di;erentiation and cell migration

• n *articular signaling y >64F *romote thesur!i!al and di;erentiation o$ do*aminergicneurons in culture, and as ale to*re!ent a*o*tosis o$ motor neurons

>64F h h i i l i



• >64F has shon *romising results in – Par8insonJs disease

– Amytro*hic -ateral 7clerosis

– Recent results# drug addiction and alcoholism treatment

• 4R34 can also e used $or Par8inson/s disease thera*yand $or e*ile*sy treatment

• 4R34 *romotes sur!i!al o$ asal $orerain cholinergic

neurons and s*inal motor neurons. 3here$ore, 4R34 hasa *otential in the treatment o$ Al?heimer/s disease andA-7

• AR34 also has a thera*eutic *ers*ecti!e, $or it isconsidered $or chronic *ain treatment

• P7P4 may e used $or the treatment o$ Al?heimer/sdisease I stro8e.



0ndor*hins # endogenous morphine

• A peptide hormone named *ndorphinproduced in the rain and anterior pituitary

• igh concentrations o$ endor*hins in the rain*roduce a sense o$ eu*horia, enhance *leasure,

and su**ress *ain, oth emotionally and*hysically.

• -o concentrations o$ endor*hins in the rain*eo*le $eel an1ious and they are also more

aare o$ *ain.



• uman ody *roduces at least E di;erentendor*hins

• al*ha (N) endor*hin

• eta () endor*hin # Most *oer$ul• gamma () endor*hin

• sigma (Q) endor*hin

C t l 4n!ironmental •Step ?4 Cue percei!ed y



y*othalamusCorticotro*in releasing $actor

(CRF)

Anterior PituitaryPro#O*iomelanocortin

(POMC)

*ndorphin +ormone

=*P>

Central 4er!ous7ystem

Cue&7tressor'

( *ain)

Step ?4 Cue percei!ed yCNS

•Step '4 Signal sent tohypothalamus =inrain>

•Step @4 +ypothalamussecretes C$F =peptide>,tra!els to pituitary

•Step 4 C$F causesprotein pro-O*iomelanocortinhormone =P)C> to eclea!ed, releases Beta

lipotropin

•Step 84 lipotropin getscon!ert into *ndorphin"

•Step 4 *ndorphin

inds to

Brain

=en C y ma t ic c lea !

age >

Beta-lipotropin

3RA47POR3 A46 673RB53O4



3RA47POR3 A46 673RB53O4

#endor*hin is released y :

1. Pituitary (into lood ) and

2. Hypothalamus ( into the s*inalcord and rain )

. Beta endorphin containing nervefires spread !idely from

neurones in the hypothalamus"

to ma#e inhiitory contacts !ith

target neurones to reduce pain.

Free hormones are rapidlyeliminated

from circulation through

+ypothalamus

F54C3O4 A7 A4A->07C



Before endorphin

release

After endorphin

release

PAIN I)P0%S* S.P B1 *ND$P+IN 4 )*C+ANIS)

h y p o t h a

l a m

u s

<A3 7 6R5> A66C3O4



<A3 7 6R5> A66C3O4 n the normal course O*iate

Rece*tors and 0ndor*hinsare 8e*t in alance ithone another.

<hen the rain is Sooded

ith e1ogenous o*iates,(heroin a mor*hinederi!ati!e) it mimic o$endor*hins so system getscon$used.

t thin8s it is ma8ing toomany endor*hins and shutsthat don, But it still has allthis e1cess (heroin) and

thin8s that it also needs to

+eroin addiction

h



<hat a**ens 4e1tT.• As more O*iate Rece*tors

are made you need moreheroin to get the samee;ect so you use more.

• And more rece*tors aremade to accommodate thee1tra hat the rain thin8sis endor*hins.

• For decreasing thise#ect- 1ou need moresustance to get the

same e#ect"

Neuro Transmitator

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