Cc cht dn truyn thn kinh

PGS.TS Cao Phi Phong

Mc tiu
1. Cc tiu chun cn thit trc khi mt phn t c phn loi nh mt cht
dn truyn thn kinh
2. C ch tc dng cc cht dn truyn thn kinh
3. Nhn dng cc cht dn truyn thn kinh quan trng
4. Nhn dng cc ri lon lm sng khi ri lon bin dng cht dn truyn thn
kinh

I. Gii thiu
A. T bo thn kinh(n-ron)
N-ron : l n v cu to c bn ca h thn kinh. Ton b h thn kinh c
khong 100 t n-ron v khong 100 t t xi-nap thn kinh(synapse) mi nron gm cc b phn sau
Thn nron(cell body): l ch phnh to ca n-ron cha bo tng, nhn v
cc bo quan: ribosom, th Nissl c mu xm, b my Golgi, lysosom, cc sc
t, ty th, ng siu vi, t thn kinh. Ni no tp trung nhiu thn n-ron th t
chc thn kinh c mu xm (v d: v no, cc nhn xm di v, cht xm
ty sng...).Thn n- ron c chc nng dinh dng, c th l ni pht sinh
xung ng thn kinh v l ni tip nhn xung ng thn kinh t ni khc
truyn n n-ron.
ui gai(dendrites): mi n-ron thng c nhiu ui gai, chia lm nhiu
nhnh, b phn ch yu tip nhn xung ng thn kinh truyn n nron.

Si trc(axon): si trc v ui gai to nn dy thn kinh v cht trng ca

h thn kinh, mi n-ron ch c mt si trc, l b phn duy nht dn truyn
xung ng thn kinh i ra khi n-ron. ng knh ca cc si trc t 0,5 m
n 22 m. V ca si trc (axolemme) c tt c cc si trc c myelin v
khng myelin. Bao myelin c hnh thnh do cc t bo Schwann c gi l
eo Ranvier. Khong cch gia hai eo Ranvier di khong 1,5 - 2 mm. Bao
myelin c xem l cht cch in, cn mng ti eo Ranvier li c tnh thm
cao i vi cc ion, to iu kin thun li cho vic dn truyn hng phn
theo si trc c nhanh chng. Phn cui si trc c chia nhnh, cui mi
nhnh c ch phnh to ra gi l cc tn cng. Cc tn cng l b phn ca nron tham gia cu to mt cu trc c bit gi l xi- np (synapse).

Hnh 1: s cu to n-ron

B. Knh ion
S vn chuyn qua mng t bo lin quan n 2 loi protein mng, l
knh v bm. Knh cho cc ions i qua theo chiu gradient nng , vn
chuyn th ng hay khuch tn c h tr. Knh ny khng th m lin tc,
thng xuyn ng v ch m ra khi c ligand gn vo (ligand-gated) hoc c
s thay i in th mng t bo (voltagegated). Nhng knh ligand-gated, v
d th th acetylcholine mng sau xi-nap, c m ra bi cht dn truyn
thn kinh acetylcholine; cn nhng knh voltage-gated Natri v Kali th li
c m ra bi s kh cc mng t bo. C 2 loi knh ion, phn theo tc
nhn lm m cng, l:
- Ligand/cAMP/cGMP gated ion channel
- Knh ion cng in th (Voltaged gated ion channel)

C. in th ng v in th ngh
T bo loi ng vt c v, 98% K+ trong t bo, Na+ th ngc li. S khc
bit v nng m bo cho 1 lot qu trnh sinh hc xy ra, c duy tr bi
bm Na+-K+ATPase. Tuy nhin, mc d ch c 2% K+ hin din ngoi t bo,
nng K+ ngoi bo ny ng vai tr rt quan trng duy tr in th ngh ca
mng t bo. S ng v m ca nhng knh c cng ion, bnh thng ng
trong thi ngh, v m p ng li vi nhng thay i in th mng, to ra
nhng gradient in ho hc. Mt xung thn kinh c to ra bi mt sng kh
cc/ti cc ngn ngi ca mng, ngang qua t bo thn kinh gi l in th
ng.
Mi thng tin i vo v i ra khi h thn kinh u c truyn qua n-ron
di dng cc xung ng thn kinh. Cc xung ng ny truyn i theo mt
chiu nht nh nh chc nng dn truyn ca cc xi-np. Xung ng thn
kinh truyn i trong n-ron theo c ch in hc cn xi-np theo c ch ha
hc.

in th ngh ca mng n-ron: trng thi ngh, mt trong v ngoi

mng n-ron c s phn b 3 ion Na+, K+ v Cl- khc nhau (mmol/L):

Do bm Na+ v K+cn gi l bm sinh in nm trn mng t bo, khi bm

hot ng, 3 ion Na+ c a ra ngoi trong khi ch c 2 ion K+ i vo bn
trong. S phn b khc bit lm mt trong mng n-ron c in th thp hn
mt ngoi 70mV v gi l in th ngh (-70mV).
in th ng ca mng n-ron: khi c mt kch thch ngng tc
ng ln mng n-ron, ti im kch thch, tnh thm ca mng i vi Na+
tng ln, lung Na+ t i vo lm in th bn trong mng tng ln cao
hn in th bn ngoi 35mV v c gi l in th ng (+35mV). in
th ng va xut hin th lp tc c truyn i trong n-ron theo c ch
nh sau: Khi mt im trn mng n-ron b kch thch th ti chuyn sang
in th ng (+35mV) trong khi nhng im gn vn trong tnh trng
in th ngh (-70mV). V vy c s chnh lch v in th v tr thnh tc
nhn kch thch nhng im xung quanh chuyn sang in th ng, tip tc
kch thch cc im k tip. C nh vy, in th ng c truyn i khp
n-ron v c gi l s dn truyn xung ng thn kinh.Tuy nhin, lung
xung ng thn kinh ch truyn n cc ui gai.

D. Dn truyn qua xi-nap

Cc tn cng (terminal button): Khi mt n-ron c kch thch, mt xung
thn kinh s di chuyn thng qua si trc cho n cc tn cng. Gia im
kt thc ca si trc gi tn hiu v n-ron nhn tn hiu, c mt khong nh
c gi l xi-nap. cc tn cng ca si trc( tin xi-nap) c cc nang nh
cha cht dn truyn thn kinh

(neurotransmitter). Cc cht dn truyn thn kinh l nhng cht ha hc cho

php cc n-ron gi tn hiu qua khe xi-nap ti n-ron khc hay cc c quan
ch (hu xi-nap). Mng hu xi-nap c cc th th (receptors). Cc th th
c cu hnh sn, do ch c mt vi cht dn truyn thn kinh nht nh
l khp vi chng. Khi mt cht dn truyn thn kinh khp vi mt th th,
mt thng ip c th c gi ti n-ron nhn (hu xi-nap).

Hnh 2: s xi-nap thn kinh

II. Cht dn truyn thn kinh

A. Lch s
u th k 20, cc nh khoa hc vn cho rng phn ln s lin lc gia cc
xi-np trong no l do in. Ramony Cajal (18521934) kho st m hc
pht hin ra gia cc n-ron c mt khe h rng t 20 n 40 nm, ngy nay

gi l khe xi-nap. S tn ti ca khe h ny dn n suy on rng s lin

lc gia cc xi-np din ra l do cc tn hiu ha hc c truyn qua khe
xi-np. Nm 1921 nh dc l hc ngi c Otto Loewi (18731961) xc
nhn rng cc n-ron c th lin lc vi nhau bng cch gii phng cc cht
hc hc. Ngoi ra, Otto Loewi c xem l ngi pht hin ra
acetylcholine(ACh) cht dn truyn thn kinh u tin

B. nh ngha cht dn truyn thn kinh

Cht dn truyn thn kinh l cht ha hc ni sinh c nhim v dn truyn
cc tn hiu qua tip hp thn kinh(xi-nap) n t bo ch, cc cht dn
truyn c cha trong ti, tp trung thnh nhm u tn cng ca si trc,
vng tin xi-nap. S phng thch cc cht dn truyn thn kinh v khuch
tn qua khe xi-nap gn vo th th chuyn bit nm trn mng hu xi-nap
thng theo sau in th ng c truyn n xi-nap v ngay c khi khng
c kch thch in

C. Tiu chun cht dn truyn thn kinh

Mt cht ha hc c xem l mt cht dn truyn thn kinh nu chng tha
mn cc iu kin sau:
+ C cc tin cht hoc/v cc enzym tng hp ca cht trn vng tin
xi-nap
+ Cht c mt trong thnh phn ca vng tin xi-nap.
+ Kch thch thn kinh gy phng thch cht dn truyn
+ Cht c mt trong n-ron tin xi-nap vi mt lng tc ng
ln nron hu xi-nap.
+ C cc th th ca cht nm vng hu xi-nap.
+ C mt c ch ha sinh lm bt hot cht .
+ Cc thuc lm gim kch thch thn kinh cng lm gim tc ng dn
truyn tng t

III. C ch tc ng ca cht dn truyn thn kinh

Cht dn truyn thn kinh i t tin xi-nap n hu xi-nap, th th lin kt vi
knh ion v enzyme, hot ng trong vi phn nghn dy. Tc ng trn c
receptor tin v hu xi-nap

Hnh 3: khe xi-nap, th th mng hu xi-nap

Cht DTTK ni kt vi th th mng hu xi-nap c th to ra tn hiu in kch
thch hay c ch (EPSP hay IPSP). Tc ng ty thuc vo ion qua mng t bo
nhiu hay t v ko di bao lu v knh chn lc (Na+ selective, K+ selective
hay Cl- selective)

By giai on tc ng ca cht dn truyn thn kinh

Cht dn truyn c tng hp t tin cht di tc ng ca enzymes
c cha trong ti
Cc phn t dn truyn thn kinh c thot ra t cc ti b ph hy bi cc
enzymes
in th ng lm ti nng chy ra xi-nap v phng thch dn truyn thn
kinh
Mt s ni kt th th t ng v c ch phng thch cht dn truyn thn
kinh tip theo sau

 Phn cn li ni vi recptor hu xi-nap

Cht dn truyn thn kinh phng thch mt hot ng c bi s ti hp thu
hay thoi ha bi enzyme

Mt vi c ch tc ng ca thuc
Thuc tc dng ng vn
Tng tng hp cht dn truyn thn kinh( gia tng tin cht)
Tng cht dn truyn thn kinh bi ph hy enzymes thoi ha
Tng phng thch cht dn truyn thn kinh(DTTK) nt tn cng
Kt ni th th t ng v chn tc dng c ch phng thch cht DTTK
Kt ni th th hu xi-nap v c hot ha hay gia tng tc ng ca cht
DTTK
Chn bt hot cht DTTK bi c ch ti hp thu hay thoi ha

Thuc tc ng i vn
Thuc c ch tng hp cht DTTK(nh ph hy tng hp cc enzymes)

 Thuc gy r ra cc cht DTTK t cc ti v ph hy bi cc enzymes thoi

bin
Thuc chn phng thch cht DTTK t nt tn cng(terminal buttons)
Thuc hot ha cc autoreceptor v c ch phng thch cht DTTK
Thuc chn th th, kt ni th th hu xi-nap v chn tc ng ca cht
DTTK

Hnh 4: S chuyn ha cht DTTK

IV. Phn loi cht dn truyn thn kinh

A. Phn loi theo nhm
C nhiu cch phn loi cht dn truyn thn kinh, ph bin l chia ra lm cc
acide amin, cc peptide v monoamin, cc nhm ln ca cht dn truyn thn
kinh:

Cc acide amin: glutamate, aspartate, D-serin, acide gamma

aminobutyric(GABA), glycine

Cc monoamin v cc amin sinh hc khc: dopamine(DA), norepinephrine(NE),

epinephrine (adrenalin), histamine, seretonin(SE, 5-HT)

Cc peptid: somatostatin, cht P, cc peptid opioid

Cc cht khc: acetylcholine(ACh), adenosin, anandamid, nitric oxid

Ngoi ra, trn 50 peptid c hot tnh thn kinh c pht hin, v s lng
trn vn cn tip tc tng. Trong nhiu cht c gii phng ng thi vi
mt cht dn truyn phn t nh, nhng phn ln cc trng hp peptid mi
l cht dn truyn chnh ti xi-np. Beta- endorphin l mt cht dn truyn

thn kinh c trng, n tham gia vo cc phn ng c tnh c hiu cao vi

cc th th opioid h thn kinh trung ng.
Cc ion n nguyn t, nh km c gii phng t xi-np, i khi cng c
xem l cht dn truyn thn kinh, cng ging nh cc phn t kh nh nitric
oxid (NO), hydro sulfur (H2S), v carbon monoxid (CO). Cc cht trn khng
phi l cc cht dn truyn thn kinh do chng c gii phng t u tn
cng si trc, nhng chng khng c ng gi trong cc ti.
Cht dn truyn ph bin nht l glutamate, l mt cht kch thch ti hn
90% cc xinp trong b no ngi. ng th hai l GABA, l cht c ch ti
hn 90% cc xi-np khng dng glutamate lm cht dn truyn. Mc d cc
cht dn truyn khc c mt ti cc xi-np t hn, chng c th co chc nng
rt quan trng. Phn ln cc thuc c tc ng n tm thn (psychoactive
drug) pht huy tc dng bng cch thay i cc hot ng ca mt vi h
thng cc cht dn truyn thn kinh, thng l tc ng qua cc cht dn
truyn khc glutamate v GABA. Cc thuc gy nghin (additive drug) nh
cocain v amphetamin pht huy tc dng ca chng ch yu ln h
dopamine. Cc thuc gy nghin h opiate pht huy tc dng ca chng
tng t nh cc peptid opioid, tc l tham gia iu ha lng dopamine.

B. Phn loi theo sinh ha

Cc

cht DTTK phn t nh (tc dng nhanh & p ng

cp tnh)
Nhm 1: Acetylcholine (Ach)

Nhm 2: Biogenic amine

+ Catecholamin: epinerphrine, norepinephrine, dopamine
+ Serotonin
+ Histamine
Nhm 3: cc cht DTTK Amino acid

+ Gamma-aminobutyric acid(GABA)
+ Glycine
+ Glutamate
+ Aspartate
Nhm 4: Nitrous oxide
Cc

cht DTTK Neuropeptide (tc dng chm & hiu

qu ko di)
+ Cc peptides hot ng thn kinh(neuroactive)
+ Cc peptide tuyn yn
+ Cc peptide tc ng trn rut v no
+ Cc peptide thn kinh(neuropeptides) t cc

m khc C. Phn loi theo sinh l:

Cht kch thch v cht c ch: mt cht dn truyn thn kinh c tc dng
trc tip duy nht l kch hot mt hoc nhiu loi th th. Tc dng ny ln
t bo hu xi-np phn ln ph thuc vo loi th th chu tc dng. Cc th
th quan trng nht ca mt s cht dn truyn thn kinh (nh glutamate)
ch c tc dng kch thch, lm tng kh nng lm cho t bo ch pht ra
mt in th ng. Cc th th quan trng nht ca cc cht dn truyn thn
kinh khc (nh GABA) ch c tc dng c ch (mc d c bng chng cho
thy GABA c tc dng kch thch trong giai on pht trin sm ca no).
Cc cht dn truyn thn kinh khc, nh acetylcholine, va c th th kch
thch va c th th c ch; v c mt s loi th th gy ra cc tc ng ln
t bo hu xi-np hot ha cc con ng chuyn ha phc tp m khng
r c tc ng kch thch hay c ch. Do , vic phn loi mt cht dn
truyn thn kinh l kch thch hay c ch rt hay c s dng.

 Cht DTTK kch thch

+ Acetylcholine
+ Aspartate
+ Dopamine
+ Histamine
+ Norepinephrine , epinephrine
+ Glutamate
+ Serotonin
Tc ng:
Trn n-ron: in th ng
Trn c: co c
Trn cc tuyn: bi tit
Trn h thn kinh trung ng: kh cc mng hu xi-nap (depolarization
of postsynaptic membrane(EPSP)
Cht DTTK c ch
+ GABA
+ Glycine
Tc ng: gim hay chn hot ng t bo hu xi-nap
Trn h thn kinh trung ng: tng s phn cc mng hu xi-nap
(hyperpolarization of postsynaptic membrane (IPSP)

IV. Cc cht dn truyn thn kinh quan trng

ACETYLCHOLINE:

Hnh 5: cu trc n-ron cholinergic

+ Dng trong tip hp thn kinh c

+ Sympathetic v parasympathetic ganglia h thn kinh ngoi bin
+ Phn hy bi Acetylcholine esterase (AChE)
+ cholinergic n-ron c ChAT enzyme (choline acetyl transferase )
Tc dng acetylcholine: dn mch, c ch tim, nhu ng rut, kim sot ngh,
kh sc, gic ng, c, bng quang v tuyn m hi. Acetylcholine kch thch
hay c ch gic ng v chu k tnh to.

Acetylcholine agonists c ch acetylcholinesterase ng dng quan trng trong

iu tr:
- glaucoma: gia tng trng lc c iu tit mt
- myasthenia gravis: c ch acetylcholine esterase (e.g., pyridostigmine,
neostigmine) ko di tc ng acetylcholine.
- Alzheimers disease tacrine dng iu tr alzheimers disease ko di c ch
cholinesterase.
Acetylcholin cht dn truyn trong h thn kinh trung ng

Tr nh (ChEI in Alzheimers disease)

Basal forebrain n cortex/hippocampus (A)

p ng vn ng ngoi thp (Extrapyramidal motor responses ) (benztropine for

Parkinsonian symptoms)

Striatum (B)

Kim sot tin nh (scopolamine patch cho say sng (motion sickness)

Hnh 6: cht dn truyn thn kinh substantia nigra v caudate - putamen

CATECHOLAMINES :
Dopamine, epinephrine, norepinephrine,
Tng hp catecholamines

+ Xut pht amino acid tyrosine tin cht thng dng

+ Ly li bi reuptake n cc tn cng hay quanh t bo thn kinh m

+ Mono-amine oxidase (MAO) v catechol o-methyltransferase (COMT) enzyme
thoi bin catecholamines
+ Tc nhn chng lo u (Anti-anxiety agents- MAO-inhibitors)

DO NOT MIX SYMPATHOMIMETICS WITH MAOIs!

(khng kt hp thuc IMAO v thuc ging giao cm)

Catecholamines trong h thn kinh trung ng

Chc nng catecholamines

Cc catecholamine thc hin cc tc ng kch thch v c ch trong h thn
kinh ngoi bin cng nh h thng thn kinh trung ng.

+ Tc ng kch thch nh: tng nhp tim, tng co bp c tim v kch thch hot
ng h hp v tm thn vn ng, kch thch da v mng nhy bng cch cung
cp mu qua s gin mch.
+ Tc ng c ch trn c trn thnh ng tiu ho, ph qun phi cng nh
cc mch mu cung cp mu cho c xng.
+ Catecholamine lm tng chuyn ho ca c th nh tng mc ly gii
glycogen v tit insulin.
+ C hai loi gn kt chnh cc th th catecholamine, c t tn l alphav beta- adrenergic. Cc th th adrenergic c lin kt vi cc protein G
trong bo tng. Sau khi hot ho cc th th adrenergic, norepinephrine c
gi li ht vo trong mng xinap kt thc hot ng ca n.
+ Th th catecholamines
blockers, nh atenolol, dng iu tr tng huyt p v au ngc trong
thiu mu c tim do kch thch i vn catecholamines trn tim
2 receptor agonists nh salbutamol kch kch thch receptor
phi c dng cho gin ph qun khng kch thch 1 receptor
tim.
D2 receptors ( dopamine) antagonist nh phenothiazines v
haloperidol c
dng trong iu nh thuc chng tm thn

Norepinephrine
+ Tc ng iu ha ca NE trong h thn kinh trung ng:

Thc tnh (Arousal)

Kh sc (Mood)
Kim sot huyt p (Blood pressure control)

Hnh 7: con ng n-ron noradrenergic

Ri lon bin dng phenylalanine (Phenylketonuria (PKU)

A genetic, autosomal recessive disorder (1:20,000 births)

Lack of enzyme phenylalanine hydroxylase

Inability to convert phenylalanine (aa) from the diet to tyrosine (aa)

Accumulation of breakdown products of excess phenylalanine leads to neuronal

degeneration, seizures, poor motor development and irreversible mental
retardation in a developing child.

Testing at birth in many states, also CA. Heel stick blood sample
Prevented by dietary restriction on phenylalanine. No whole protein; source of
all aas minus this one. At least through to adulthood, while nervous system is
developing

Hnh 8: S c ch tc ng ca thuc trn n-ron noradrenergic

Dopamine:

Cc con ng chnh dopaminergic(Major Dopaminergic (DA)

pathways)
+ Nigrostriatal (substantia nigra to striatum)

+ Mesolimbic/mesocortical (ventral tegmental midbrain to n.accumbens,

hippocampus, and cortex)
+ Tuberoinfundibular (arcuate nucleus of hypothalamus to median
eminence then anterior pituitary)

Hnh 9: cc con ng n-ron dopaminergic

iu ha h thn kinh trung ng ca DA

Bao gm: movement, memory, pleasurable reward (cm gic hi lng), behavior
and cognition, attention, inhibition of prolactin production, sleep, mood, learning
Nigrostriatal (substantia nigra to striatum)
+ Kim sot vn ng ngoi thp (extrapyramidal motor control)
Mesolimbic/mesocortical (ventral tegmental to n.accumbens, hippocampus, and
cortex)
+ Cm xc (emotion)
+ Nhn thc (cognition)
Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then
anterior pituitary)
+ Prolactin (prolactin release)

Amine no v bnh l

+ Biogenic amine theory of depression (hc thuyt v trm cm ca biogenic

amine): thuc chng trm cm c ch ti hp thu 5HT hay NE

Hnh 10: c ch tc dng thuc chng trm cm

+ Dopaminergic theory of schizophrenia (hc thuyt tm thn phn lit):

thuc u tin iu tr tm thn tc dng i vn th th D2

Hnh 11: c ch tc ng thuc chng tm thn

+ Dopaminergic involvement in Parkinsons disease(bnh Parkinson)
+ Parkinson like symptoms are side effects of DA receptor blockade
with antipsychotic drugs (triu chng ging Parkinson do tc dng ph
chn th th DA vi thuc chng tm thn)
+ MPTP, a neurotoxin, destroys DA neurons and induces PD (MPTP,
nhim c thn kinh, ph hy n-ron DA gy bnh Parkinson)
Parkinsons Disease (Parkinsonism): mt dopamine t n-ron substantia
nigra trung no (midbrain), Resting tremor, pill rolling, bradykinesia,
gait. iu tr Ldopa. (Crosses BBB) hay MAO inhibitors.

Hnh 12: tn thng substantia nigra trong bnh Parkinson

Chc nng ca DA
+ kim sot vn ng (parkinsonism)
+ gy i
(Similar dopamine antagonist drugs are also some of the most effective antinausea agents. Restless legs syndrome and attention deficit hyperactivity
disorder (ADHD) are associated with decreased dopamine activity)
+ c ch tit prolactin
(Dopamine is the main neuroendocrine inhibitor of the secretion of prolactin
from the anterior pituitary gland)
+ GnRH (Gonadotropin-releasing hormone (GnRH), hay luteinizing hormonereleasing hormone)
+ Tm thn phn lit (schizophrenia)
+ Dopamine c tc dng kch thch: hot ha nhn thc, p ng iu ha cm
xc.
+ Dopamine v nghin

(Cocaine and amphetamines inhibit the re-uptake of dopamine. Cocaine is a

dopamine transporter blocker that competitively inhibits dopamine uptake to
increase the presence of dopamine.
Amphetamine increases the concentration of dopamine in the synaptic gap,
but by a different mechanism. Amphetamines are similar in structure to
dopamine, and so can enter the presynaptic neuron via its dopamine
transporters. By entering, amphetamines force dopamine molecules out of
their storage vesicles. By increasing presence of dopamine both these lead
to increased pleasurable feelings and addiction.)

SEROTONIN(5-Hydroxytryptamine-5-HT):

Hnh 13: n-ron serotoninergic

+ Tng hp t tryptophan

+ Cn c bit nh 5-hydroxytryptamine (5-HT)

+ SSRI- selective serotonin reuptake inhibitors l anti-depressant
+ Gy kch thch nhiu hn gim cm gic sng khoi (Ecstasy causes
more release!)
+ Cht DTTK tng kh sc (Mood elevator, feel-good neurotransmitter)
-

Serotonin ngoi bin: 98% trong mu v c trn

Trong h thn kinh trung ng: nhn Raphe, di i

5HT1 v 5HT2
Chc nng
+ iu ha: hp thu carbohydrate v phng thch hormone hypothalamic
+ c ch au
+ o gic v 5HT
+ Kh sc

Hnh 14: mi lin h lm sng ca serotonin

Thuc chng trm cm

iu tr trm cm c th bao gm: tricyclic anti-depressants, c ch

uptake c noradrenaline v adrenaline vo trong t bo no hay

antidepressants khc nh fluoxetine (prozac) c ch serotonin
uptake, c ch monoamine oxidase A
Serotonine, Dopamine (DA) v catecholamine khc nh Noradrealine

(NA) c coi l c vai tr quan trng trong bnh sinh cc ri lon trm
cm.
1.MAOI (Monoamino oxydase inhibitor):
MAOI c in (1952).
C 4 loi ang c dng ph bin M hin nay l:
-

Selegiline

Tranylcypromine (Parnate)

Phenelzine (Nardil)

Marplan
MAOIs mi: Brofaromine (Consonar); moclobemide (Aurorix) l loi thuc
c ch c hi phc (reversible inhibitor) men monoaminooxidase

2. Thuc chng trm cm 3 vng (Tricyclic

Antidepressant) (1957). - m du, gii lo u: Amitriptiline,
Elavil, Laroxyl, Triptizol...
- tc dng hot ho, kch thch mnh: Melipramin, Imipramin, Nortriptiline,
Tofranil. - trung gian (Anafranil) c ch ti hp thu chn lc serotonin, cu
trc ho hc li ging CTC 3 vng .
3. Loi khng 3 vng, khng IMAO.
+ SSRI (Selective serotonin reuptake inhibitor)
SSRIs approved by the Food and Drug Administration (FDA) to treat
depression, with their generic names followed by brand names in
parentheses, include:

- Citalopram (Celexa)
- Escitalopram (Lexapro)
- Fluoxetine (Prozac)
- Paroxetine (Paxil, Pexeva)
- Sertraline (Zoloft)
Paxil CR is an SSRI that provides controlled release of the medication
throughout the day or for a week at a time with a single dose.
SSRIs cng c th dng iu tr cc ri lon khc hn trm cm nh ri lon lo
u. SSRI l loi thuc chng trm cm mi (1984), bt u s dng rng ri trn
th gii.
+ SNRI (Serotonin and norepinephrine reuptake inhibitors):
SNRIs are a class of medications that are effective at easing depression
symptoms. SNRIs are also sometimes used to treat other conditions such as
anxiety and nerve pain.
The Food and Drug Administration (FDA) has approved these SNRIs to treat
depression:
- Duloxetine (Cymbalta)
- Venlafaxine (Effexor XR)
- Desvenlafaxine (Pristiq)

*p-chlorophenylalanine (PCPA): inhibitor tryptophan hydroxylase (TPH)

* The vesicular monoamine transporter (VMAT) is a transport protein integrated into the
membrane of synaptic vesicles of presynaptic neurons.

Hnh 15: Tc dng thuc trn n-ron serotoninergic

HISTAMINE

Histamine v Histamine Receptors

+ Histamine l phn t nh xut pht t decarboxylation ca amino
acid histidine. c ph hy bi enzyme diamine oxidase
+ Histamine c tng hp trong tt c cc m, c bit phong ph
da, phi v ng tiu ha. Mast cells hin din trong nhiu m,
ngun ch lc histamine, nhng cng c sn xut t cc t bo min
dch khc
+ Histamine c cng nhn nh neurotransmitter trong h thn kinh
trung ng ch trong 15 nm qua
+ N-ron histaminergic bi tit histamine khu tr vng nh di i v
cho si trc n nhiu vng ca no. Histamine iu ha mt s qu trnh
quan trng no nh:
- s thc tnh (wakefulness),
- kh nng nhn thc (cognitive ability)
H1 receptors antagonists: diphenhydramine dng trong iu tr p ng d
ng (allergic responses )
H2 receptors antagonists : ranitidine hay cimtidine iu tr peptic ulcers.
H2 receptor inhibitors khng nh hng allergy.

Histamine trong h thng tin nh

+ Cht DTTK nh hng tin nh cn hiu bit rt t?
+ Histamine(H1-H3) tm thy nhiu ni trong cu trc tin nh trung ng (nh
hng khng histamines trong iu chnh triu chng chng mt bun nn
(motion sickness)
(Takeda et al, 1989).
+ C 2 th th histamine H1 v H2: p ng tin nh
(Serafin et al, 1992).
+ Th th H3 l th th t ng (autoreceptor) v nh hng H1 v H2.
+ Th th H4 nh hng nron tin nh ngoi bin(primary vestibular neurons)
Khng histamine
+ Cc khng histamine ch yu H1 receptor antagonist nhng cng c tc dng
anticholinergic, tc dng c trung ng v ngoi bin.
+ Cc khng histamine khng qua hng ro mu no, ch li trong iu tr chng
mt ?
+ Tc dng an thn do anticholinergic ( meclizine)
+ Antihistamine gy c ch h thn kinh trung ng

GABA v GLYCINE(Amino Acid Neurotransmitters)

Hnh 16: n-ron GABAnergic

Chc nng ca GABA
+ cht DTTK c ch chnh trong h thn kinh trung ng
+ gim GABA gy cn ng kinh(GABA-seizures)
+ chng ng kinh ch GABA receptors hay tc ng nh GABA agonists
+ Valium gia tng vn chuyn GABA ti xi-nap

GABA trong h thn kinh trung ng

+ ng Nigrostriatal

p ng extrapyramidal motor

+ Interneurons khp ni trong no

c ch cc kch thch, n nh in th mng t bo, phng nga

phng in lp li (repetitive firing)

Dc l hc ca GABA receptor
Cht dn truyn thn kinh c ch chnh trong h thn kinh trung ng
Hai loi receptors
+ GABAA sau xi- np, v tr chuyn bit, lin kt knh CI+ GABAB autoreceptors tin xi- np, gim phng thch dn truyn qua gim
calcium influx, postsynaptic ni vi G-proteins gia tng dng K+

Hnh 17: th th GABA

Th th GABAA lin h cn ng kinh

+ Mt s truyn ng GABA-ergic gp phn khch thch qu mc v lan rng

xung ng trong ng kinh.
+ Picrotoxin (GABA receptor blocker) c ch chc nng GABAA v gy co git.
+ BDZs v barbiturates gia tng chc nng th th GABAA v gy chng ng
kinh.
+ Thuc chn GABA reuptake (GAT) v gia tng bin dng( GABA-T) GABA
sn sng s dng tc dng chng ng kinh
+ Cc thuc chng hi hp( anxiolytic drugs ): diazepam v barbiturate,
gy ng v chng ng kinh dng trong iu tr ng kinh, tc ng m du
do ni kt GABA n GABA-A receptors.

Hnh 18: C ch cc thuc chng ng kinh trn n-ron GABAnergic

Hnh 19: V tr tc ng ca benzodiazepine

GLYCINE
+ Glycine cng l cht c ch
+ Hu ht trong ty sng v n-ron vn ng thn no
+ Glycine receptor l ionotropic chloride channel tng t GABAA receptor.
+ Strychnine, competitive antagonist ca glycine, ly i c ch ty sng ti
c vn v gy p ng vn ng mnh
Metabotropic GABAB receptor

Th th ny l GPCRS (G proteincoupled receptors (GPCRs)

Phn ln tin xi-nap, c ch phng thch dn truyn (Largely presynaptic, inhibit

transmitter release)

Vai tr quan trng nht trong ty sng

Baclofen, agonist ti th th ny, gin c

GLUTAMATE
+ Cht DTTK ca 75-80% cc xi-nap h thn kinh trung ng
+ Tng hp trong no t Glucose (via KREBS cycle/-ketoglutarate),
Glutamine (from glial cells)
+ Hot ng cui cng l hp thu vo n-ron hay thn kinh
m(astrocytes) thng qua excitatory amino acid transporters (EAATs)
+ Th th antagonists Glutamate gip ngng cht n-ron sau t qu
+ Nhiu excitotoxicity gy mt iu chnh calcium influx
+ t dn n psychosis (delusional, paranoid, lack of contact with reality)

Hnh 20: Cc th th ca glutamate

Dc l hc ca glutamate receptor
+ Glutamate c phng thch qua khe xi- np v tc ng th th AMPA v
NMDA,
+ M knh AMPA cho php s i vo ion Na+ kh cc mng t bo v
in th qua mng t bo hng v dng tnh.
+ Vi kh cc, phng thch Mg

2+

t th th NMDA cho php ion Na+ v

Ca 2+ vo trong nron sau xy np. in th kch thch sau xy np c

to ra(EPSP)

Hnh 21: in th kch thch v c ch hu xi-nap

c im NMDA Receptor
+ Chn in th ngh ca mng (Blocked at resting membrane potential
(coincidence detector)
+ i hi kt ni glycine
+ Thm Ca++ cng nh Na
NMDA receptors lin h trong bnh
+ cn ng kinh
+ hc tp v tr nh
+ cht n-ron

Thiu mu

Hnh 22: NMDA receptors trong kch thch c hi cht t bo

( excitotoxic cell death)

Hnh 23: Thuc gy c ch ng kinh trn NMDA& AMPA receptor

V. Cc cht DTTK v bnh l

Nhiu cc cht DTTK quan trng c lin quan ti cc ri lon tm thn, bao
gm dopamine, serotonin, norepinephrine, v gamma-aminobutyric acid
( GABA). Serotonin v dopamin lin h trm cm, hng cm (mania), v tm
thn phn lit (schizophrenia). Norepinephrine l cht dn truyn thn kinh
m nhn vai tr giao tip vi h thn kinh cng giao cm , lin quan ti cc
trng thi bn chn, kch thch cao c th gy ra chng ri lon lo u v
cc tnh trng lin quan ti cng thng khc. GABA cn tr cc xung thn kinh
chy khp no b v c lin quan ti ri lon lo u.

Hnh 24: vai tr cht DTTK trong bnh tm thn

Cc l thuyt trc y lin h cc cht dn truyn thn kinh vi cc ri lon
tm thn cho rng, mt vi ri lon c gy ra bi hoc l qu nhiu, hoc
l qu t mt s cht DTTK (v d: hng cm lin quan ti qu nhiu
norepinephrine, ri lon lo u th li c qu t GABA). Cc cht dn truyn
thn kinh c tng hp trong n-ron thng qua mt lot cc bc trao i
cht, bt u vi amino acid. Mi mt phn ng khi ang sn xut ra cht
dn truyn thn kinh th u c xc tc bi mt enzyme. Qu nhiu hay
qu t mt s cht dn truyn thn kinh c th gy ra li trong qu trnh trao
i cht. V d, tht bi trong vic reuptake cc cht dn truyn thn kinh
cn li tr v vi nhn ca n-ron gi (ti hp thu) s li mt lng d
tha cc cht dn truyn thn kinh trong xi-nap. Sau , nu c mt xung

thn kinh dn n vic nhiu cht dn truyn thn kinh c truyn ti cc

xi-nap, cc n-ron nhn s gn nh l c gp i lng cht ha hc ny, t
lm tng kh nng to ra mt xung thn kinh mi.
Cc nghin cu tp trung vo kh nng cc th th ca cc dn truyn thn
kinh l c li chnh trong vic gy ra cc ri lon tm thn. Nu nh cc th
th cc n-ron nhn qu nhiu hoc qu d b kch thch, kt qu s tng
t nh vic c qu nhiu lng cc cht dn truyn thn kinh c gi i. V
d nhng o tng (delusions) v o gic (hallucinations) ca chng tm
thn phn lit, c th l kt qu ca vic qu ti lng th th dopamine.

Rt nhiu phng php kim sot c nhy cm ca cc n-ron nhn.

V d nu mt th th c hot ng qu lu, nhn ca n-ron c th iu
chnh li nhy ca th th khin cho n kh to ra xung thn kinh hn. Khi
mt nhn bt u pht ra cc xung hoc tn hiu nhiu hn, th th ny s
gii phng nhng thng ip th hai (second messengers). Mt khi thng
ip ny c gii phng, chng ng vai tr trong vic iu chnh nhy
ca cc th th ca n-ron nhn vi dopamine, norepinephrine, hay
serotonin. Mt s ngi c th cho rng nhng thng ip th hai ny nh l
mt dng n-ron gip chnh sa nhy ca th th khi n tr nn qu kch
hot .

Mt vi phng php khc dng nghin cu v hot ng ca cc cht

dn truyn thn kinh trong no b l cho ung cc loi thuc gy kch thch
mt vi th th nht nh cc cht dn truyn thn kinh, cn c gi l
agonist (cht khi to mt phn ng sinh l khi kt hp vi th th). V d
mt serotonin agonist, l mt loi thuc gip kch thch cc th th serotonin
sn sinh ra nhng hiu ng tng t nh serotonin t nhin. Ngc li,
mt antagonist (cht i khng) l loi thuc ch hot ng trn cc th th
ca cht dn truyn thn kinh, c tc dng c ch cc hot ng ca n. V
d, cc loi thuc dng cha tr bnh tm thn phn lit l dng i
khng dopamine gip chn nhng th th dopamine li.