Tổng quan về vai trò dopamin trong não và hiệu quả của morphin-amphetamin trong não chuột thực nghiệm.pdf

B Y T

TRNG I HC DC H NI

NGHIM TH THY LINH

TNG QUAN V VAI TR DOPAMIN

TRONG NO V HIU QU CA

MORPHIN/AMPHETAMIN TRN

NNG DOPAMIN TRONG NO

CHUT THC NGHIM

KHA LUN TT NGHIP DC S

H NI 2013

B Y T

TRNG I HC DC H NI

NGHIM TH THY LINH

TNG QUAN V VAI TR DOPAMIN

TRONG NO V HIU QU CA

MORPHIN/AMPHETAMIN TRN

NNG DOPAMIN TRONG NO

CHUT THC NGHIM

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. TS. Nguyn Thnh Hi Ni thc hin

1. B mn Dc Lm Sng i hc dc H Ni.

H NI 2013

LI CM N

Trc tin, cho php ti xin gi li cm n chn thnh v su sc ti:

TS. Nguyn Thnh Hi B mn Dc lm sng Trng i hc Dc H Ni.

L ngi thy tn tnh hng dn v gip ti trong sut qu trnh thc

hin kha lun ny.

Ti xin gi li cm n ti Ths. Trnh Trung Hiu, ngi ng h v c

nhng ng gp qu bu gip ti tip cn phng php nghin cu mi - phng

php tng quan h thng.

Ti cng xin gi li cm n chn thnh ti TS. Phm Hng Ln, Vin K thut

Ha-Sinh v Ti liu Nghip V, B Cng An v nhng gp qu bu lm cho

ti c ngha thit thc hn trong cng cuc phng chng ma ty.

Ti xin cm n cc thy c B mn Dc lm sng to iu kin ti c

th thc hin kha lun ny.

Ti cng xin gi li cm n ti Ban gim hiu, cc Phng ban Trng i

hc Dc H Ni cng ton th cc thy c gio trong trng cho ti nhng

kin thc qu bu trong qu trnh hc tp ti trng.

Cui cng, ti xin gi li cm n su sc ti gia nh v bn b lun bn

cnh, ng vin ti trong lc kh khn cng nh trong qu trnh thc hin kha

lun ny.

H ni, ngy 21 thng 5 nm 2013

Sinh vin

Nghim Th Thy Linh

MC LC

DANH MC CC K HIU, CC CH VIT TT

DANH MC BNG

DANH MC CC HNH V

T VN ........................................................................................................ 1

CHNG 1: TNG QUAN V VAI TR CA DOPAMIN, CC CHT MA

TY V NGHA KHOA HC LIN H DOPAMIN VI CC CHT MA

TY ........................................................................................................................ 3

1.1. DOPAMIN V VAI TR DOPAMIN .......................................................... 3

1.1.1. Khi nim dopamin........................................................................................ 3

1.1.2. Vai tr ca dopamin ....................................................................................... 5

1.1.2.1. Vai tr dopamin trong hnh vi nhn thc ................................................ 5

1.1.2.2. Vai tr dopamin trong vic to hnh vi cm xc khi s dng ma ty ...... 7

1.2. MA TY V TC DNG CA MA TY .................................................. 11

1.2.1. Khi nim v ma ty .................................................................................... 11

1.2.2. Phn loi cc cht ma ty ............................................................................. 12

1.2.2.1. Phn loi theo tc dng ca cht ma tu ............................................... 12

1.2.2.2. Phn loi theo ngun gc sn sinh ca cht ma tu ............................... 13

1.2.3. Tc dng ca ma ty .................................................................................... 13

1.3. NGHA KHOA HC LIN H GIA DOPAMIN V CHT MA

TY.. .................................................................................................................... 14

1.3.1. Nghin cu c ch tc dng phn t ca cc cht ma ty v c ch cai nghin

ca cc thuc mi. ................................................................................................. 14

1.3.2. Nghin cu phng php thm nh hiu qu tc dng ca cc cht ma ty 16

CHNG 2: TNG QUAN H THNG V HIU QU CA

MORPHIN/AMPHETAMIN TRN NNG DOPAMIN TRONG NO

CHUT THC NGHIM .................................................................................. 21

2.1. GII THIU CHUNG ................................................................................ 21

2.2. I TNG V PHNG PHP NGHIN CU ................................ 22

2.2.1. i tng nghin cu: ................................................................................ 22

2.2.1.1. Cc ngun c s d liu ....................................................................... 22

2.2.1.2. Tiu chun la chn cc bi bo ........................................................... 22

2.2.1.3. Tiu chun loi tr ................................................................................ 23

2.2.2. Phng php nghin cu:............................................................................ 23

2.2.2.1. Chin lc tm kim ............................................................................. 23

2.2.2.2. Quy trnh tm kim v la chn bi bo ................................................ 24

2.2.2.3. Ni dung thu thp t bi bo c la chn .......................................... 26

2.2.2.4. X l s liu ......................................................................................... 26

2.3. KT QU NGHIN CU.......................................................................... 27

2.3.1. S lng nghin cu cn phn tch h thng ............................................... 27

2.3.2. Hiu qu ca amphetamin trn s thay i nng dopamin trong no ...... 29

2.3.3. Hiu qu ca morphin trn s thay i nng dopamin trong no ............ 33

2.3.4. So snh hiu qu ca amphetamin/morphin n s thay i nng DA

trong no ............................................................................................................... 36

2.4. BN LUN ................................................................................................. 38

2.4.1. c im chut lm th nghim................................................................... 38

2.4.2. Liu v ng dng ca morphin v amphetamin ....................................... 38

2.4.3. nh hng ca morphin v amphetamin n nng ca dopamin trong

no.. ................................................................................................................... 38

2.4.4. Hng pht trin trong tng lai ................................................................. 40

CHNG 3: KT LUN V KIN NGH ...................................................... 42

3.1. KT LUN ................................................................................................. 42

3.2. KIN NGH ................................................................................................ 43

TI LIU THAM KHO

PH LC 1: L do v danh sch 83 bi bo b loi

PH LC 2: Danh sch 5 bi bo khng ly c ni dung chi tit (fulltext)

PH LC 3: Bi bo nghin cu khoa hc

DANH MC CC K HIU, CC CH VIT TT

A

Tin trc sau (Anteroposterior)

AMPH Amphetamin

DA Dopamin

DAT Knh vn chuyn thu hi Dopamin (Dopamin transporter)

i.v. Tim tnh mch (Intravenous)

i.p. Tim mng bng (Intraperitoneal)

L Sang tri phi (Lateral)

NAc Nhn accumben (Nucleus Accumbens)

PET Chp ct lp pht x positron (Positron emission tomography)

s.c. Tim di da (Subcutaneous)

TLTK Ti liu tham kho

V Ln xung (Ventral)

VTA Vng Ventral tegmental (Ventral tegmental area)

DANH MC BNG

Bng 1.1. Mc tng nng dopamin ti cc vng no trn chut thc nghim di

tc dng ca cc loi kch thch khc nhau .............................................................. 6

Bng 1.2. nh hng ca cc thuc n mc phong b DAT trn ngi .......... 15

Bng 1.3. Ta cy kim thm d ti cc vng no .............................................. 20

Bng 2.1. Kt qu cc nghin cu v s thay i nng DA trong no khi s dng

amphetamin trn chut cng. ................................................................................. 32


morphin trn chut cng v chut nht .................................................................. 35


morphin hoc amphetamin trn chut cng ........................................................... 37

DANH MC CC HNH V, TH

Hnh 1.1. Cc con ng dn truyn v c ch gii phng dopamin trong no ........ 3

Hnh 1.2. Nhng con ng dn truyn dopamin trong no .................................... 4

Hnh 1.3. Nghin cu PET trn s thay i mt th th DA sau khi chu tc ng

bi cc kch thch (thuc l, ru, bo ph v cocain) .............................................. 7

Hnh 1.4. Cc con ng dn truyn phn thng trong no khi s dng mt s

cht in hnh nh: Opioid, Ethanol, Barbiturat, Amphetamin, Cocain, Cannabioid,

Phencyclidin cho thy dn truyn dopamin tp trung ch yu vng nhn

accumben ................................................................................................................ 8

Hnh 1.5. C ch lm tng gii phng DA trong no ca Amphetamin .................... 9

Hnh 1.6. C ch kch thch gii phng DA ca opiat ............................................ 10

Hnh 1.7. C ch gii phng DA v to hnh vi cm xc sau khi s dng cocain .. 10

Hnh 1.8. Mt s hnh dng ca cc vin ma ty trn th trng ............................ 12

Hnh 1.9. S khe synap DA v hnh nh chp PET cc m ch khc nhau:

Knh vn chuyn thu hi DA chp vi 11C D-threo methylphenidat v th th D2

chp vi 11C raclopride ......................................................................................... 15

Hnh 1.10. S thm nh cc cht ma ty nhanh bng k thut thm tch micro

online . .................................................................................................................. 17

Hnh 1.11. S m t s dng k thut thm tch micro c cy trong cc vng

no VTA (trung tm sinh ra DA) v vng nhn Accumben (ni gii phng DA, gy

ra phn thng). ................................................................................................. 19

Hnh 1.12. Hp s ca chut nhn t trn xung .................................................... 19

Hnh 2.1. Mi lin h gia dopamin trong no, cc cht ma ty v hnh vi cm

gic ............................................................................................................ 21

Hnh 2.2. Cng c MeSH tm kim t ng ngha ................................................. 22

Hnh 2.3. S quy trnh tm kim v la chn bi bo ........................................ 25

Hnh 2.4. Kt qu la chn bi bo ........................................................................ 28

-1-

T VN

Dopamin (DA) l mt trong nhng cht dn truyn thn kinh catecholamin quan

trng c bit n. Trong b no con ngi, DA m nhim nhiu chc nng

khc nhau trong bao gm s vn ng, nhn thc [99], hnh vi cm xc [9], s tp

trung v hc tp [99, 148]. Hnh vi cm xc ca con ngi chu chi phi bi s tng

hay gim nng DA trong no. Khi chu kch thch, nng DA trong no s thay

i, t s bc l ra bng cm xc (hng phn hay trm cm). V nh vic c

n mt mn ngon, c khen ngi hay ht thuc l u lm cho nng DA trong

no tng ln, khi con ngi cm thy sng khoi, vui sng v hnh phc [36].

Ma ty c bit n nh l mt cht thn k. N mang li cho ngi s dng

cm gic d chu, sng khoi, c th qun i bun phin au n [22, 92, 123]. Tuy

nhin ma ty gy ra s l thuc v mt th cht hoc v mt tm l, c khuynh

hng tng liu v khin ngi nghin mt kim sot v hnh vi.

V c DA trong no v cc cht ma ty u c chng minh nh hng n

cc hnh vi cm xc ca con ngi, nn t lu cc nh nghin cu c gng tm ra

gi thuyt v s tn ti mi lin h gia DA vi cc cht ma ty. Vic xc nh

c mi lin h ny v chnh xc hn l mc thay i nng DA trong no

sau khi s dng cht ma ty c th gip nh gi c mc nh hng ca tng

cht ma ty i vi c th v cho php xy dng mt bn tham chiu so snh hiu

lc tc dng ca mi cht ma ty. Hn na, y cng l cn c khoa hc cho php

cc nghin cu su hn v c ch tc dng phn t v c ch cai nghin ca cc loi

ma ty mi, c ng dng thc tin i vi con ngi. Tuy nhin, hin nay cc

nghin cu ch dng mc ring l v nh gi s thay i nng DA trn no

chut thc nghim sau khi s dng mt cht ma ty, m cha c mt nghin cu

tng quan h thng (systematic review) no v mi lin h trn. Vi mc ch a

ra c bng chng khoa hc v s lin h ca DA vi cc cht ma ty, t gp

phn khng nh khng nh cho cc gi tr nghin cu sau ny, chng ti tin hnh

thc hin ti: Tng quan v vai tr dopamin trong no v hiu qu ca

-2-

morphin/amphetamin trn nng dopamin trong no chut thc nghim vi

cc mc tiu sau:

1. Tng quan v vai tr ca dopamin, cc cht ma ty v ngha khoa hc mi

lin h gia DA v cc cht ma ty.

2. Tng quan h thng (systematic review) v hiu qu ca

morphin/amphetamin trn nng dopamin trong no chut thc nghim.

-3-

CHNG 1: TNG QUAN V VAI TR CA DOPAMIN,

CC CHT MA TY V NGHA KHOA HC LIN H

DOPAMIN VI CC CHT MA TY

1.1. DOPAMIN V VAI TR DOPAMIN

1.1.1. Khi nim dopamin

nh ngha

Dopamin (DA), hay cn gi l cht to "nim vui", l mt cht dn truyn thn

kinh c bn cht catecholamin c tng hp bi cc t bo thn kinh

dopaminergic, hot ng thng qua cc th th c hiu [96], c kh nng lm tng

hoc gim hot ng ca cc t bo thn kinh. DA c rt nhiu nh hng ln no

ng vt c v, bao gm vai tr trong iu chnh kh nng nhn thc, vn ng,

khoi cm, iu ho ni tit, ghi nh v hc hi [34, 35] v c quan h cht ch vi c

ch "phn thng" thng qua con ng mesolimbic [32] (Hnh 1.1).

Hnh 1.1. Cc con ng dn truyn v c ch gii phng dopamin trong no

-4-

Phn thng (reward) l mc tiu, l khao kht m con ngi mun t c

to ra cm gic hng phn, sng khoi cho bn thn [36]. Phn thng c vai tr

rt quan trng i vi tng c nhn v n h tr cho cc hot ng thng thng

nht nh n ung hay cht lng cuc sng. C ch ca phn thng trong hnh vi

gn lin vi qu trnh hc hi v ghi nh nhng kch thch, khoi cm m ta gp

hng ngy.

Cc con ng dn truyn dopamin trong no (dopaminergic pathway)

Dopamin (DA) trong no c gii phng bi cc t bo thn kinh

dopaminergic phn b mt s vng trong no, bao gm cht en (Substantia

nigra), vng ventral tegmental (ventral tegmental area, VTA) hay vng di i [15,

28], sau c dn truyn xung ng theo dy thn kinh dopaminergic n cc

vng no cui cng (nh vng nhn accumben, vng th vn hay vng v no)

gy ra cc hnh vi nhn thc cho con ngi (Hnh 1.2).

Hnh 1.2. Cc con ng dn truyn dopamin trong no [28]

-5-

Nhng xung ng ny c truyn theo trc t bo thn kinh n nhng vng

ca no gy hnh vi nhn thc thng qua 3 con ng chnh [15] (Hnh 1.2):

- Con ng mesolimbic (mu xanh): truyn DA t vng VTA (ventral

tegmental area) n vng nhn accumben (Nucleus Accumbens hay NAc).

VTA l vng thuc no gia, v nhn accumben l vng thuc h vin no.

- Con ng mesocortical (mu vng): truyn DA t VTA n v no trc

trn (frontal cortex)

Hai con ng mesolimbic v mesocortical c th c gi chung l

mesocorticolimbic. y chnh l h thng phn thng (reward system)

trong no [148].

- Con ng nigrostriatal (mu tm): truyn DA t cht en (substantia nigra)

n cc vng quanh th vn (striatum). Con ng ny lin quan n kim sot

vn ng, gn lin vi c ch bnh sinh ca bnh Parkinson.

1.1.2. Vai tr ca dopamin

1.1.2.1. Vai tr dopamin trong hnh vi nhn thc

Dopamin (DA) ng mt vai tr quan trng trong h thng no chu trch

nhim cho qu trnh phn thng [148]. Cng tham gia vo c ch phn thng

ca no l vai tr hc hi, ghi nh v cng c ca DA [9, 148]. thy trc trn

(frontal cortex), DA kim sot s truyn thng tin t cc vng khc nhau ca no.

S ri lon DA vng no ny c th gy ra s suy gim nhn thc, c bit l tr

nh, s tp trung v kh nng gii quyt cc vn . Gim nng DA v no

trc trn gy ra ri lon s ch . Th th D1 [63] v D4 [18] chu trch nhim v tc

dng tng nhn thc ca DA. Cc nghin cu thc nghim cho thy rng tn

thng c chn lc cc t bo thn kinh dopaminergic chut cng v cc loi linh

trng c th dn n gim nhn thc, c bit l khi c s thay i con ng

mesocorticolimbic ca cc h thng dopaminergic [99].

ngi, s xut hin ca cc "phn thng" khi c tc ng bi cc cht kch

thch nh ru, thuc l, cc tr chi in t, hot ng tnh dc hay s dng cc

-6-

cht ma ty nh cocain, morphin, amphetamin, c bo co trong cc nghin

cu PET (k thut chp ct lp pht x positron, Positron emission tomography),

cho thy nng DA thay i r rt v tc ng ln cc vng nhn accumben, vng

th vn (striatum), no trc nh mt tc nhn iu chnh tc ng ca "phn

thng", lm cho con ngi c cm gic hng phn, sng khoi, gim au khi chu

tc ng ca chng (Bng 1.1).

Cc hot ng Tng dopamin (%) Vng no TLTK

Thc n ngon 137% Nhn Accumben [64]

Hot ng tnh dc 147% Nhn Accumben [48]

Khi thuc l (nicotin 0.13g/kg) 160% Nhn Accumben [45]

Ru (ethanol 1.0g/kg) 129.44% 4.9% Nhn Accumben [44]

Cocain (1.0mg/kg) 220% Nhn Accumben [23]

Bng 1.1. Mc tng nng dopamin ti cc vng no trn chut thc nghim di

tc dng ca cc loi kch thch khc nhau

Sau khi chu cc kch thch ln th nht, no s ghi nh cc phn thng

thng qua vai tr hc hi, ghi nh v cng c ca DA. iu ny cng thy r khi c

th tip tc i hi cc kch thch trong ln tip theo [59, 106, 147]. V d: i bng l

mt trng thi kch thch gip no nh n cm gic khi nhn c phn thng

t thc n mang li [78]. Cng i bng th k c v thc n cng tng ln. T

thc y con ngi thc hin hnh vi t c phn thng [148]. Cc hnh vi

ny khng ch c cng c m cn c lm cho mnh hn v nhanh hn trong

ln phn ng thng tip theo [59]. Nh vy DA cng chnh l tc nhn khuyn

khch con ngi, ng vt tm kim li cm gic hng phn, sng khoi, kch thch.

Nu khi kch thch qu mc trong mt thi gian di to ra phn thng s

lm gim ng k s lng th th DA tip nhn synap sau trn cc t bo thn

kinh dopaminergic [139, 142], trong khi cc th th DA cn li cng tr nn km

-7-

nhy hn vi tc dng ca DA (Hnh 1.3). Lc , c th s i hi tip tc tip

xc vi cc kch thch p ng nhu cu b cc th th km nhy cm vi DA,

gip to ra sng khoi, hng phn. y chnh l mt phn ca c ch gy nghin

(nghin ma ty, nghin ht thuc l, nghin game hay nghin ru) m cc nh

nghin cu ang khm ph trn con ngi.

Hnh 1.3. Nghin cu PET trn s thay i mt th th DA sau khi chu tc ng

bi cc kch thch (thuc l, ru, bo ph v cocain)

(mu cng nht th mt th th cng gim)

Ngoi ra, DA cn c vai tr trong s vn ng v lin quan n s bi tit

prolactin. S thiu ht DA cc t bo thn kinh dopaminergic c th gy ra bnh

Parkinson [102]. nhng ngi ny, h b mt kh nng thc hin cc vn ng mt

cch trn tru v kh kim sot s chuyn ng [72]. ng thi DA l hormon chnh

c ch s bi tit prolactin t thy trc tuyn yn [15].

1.1.2.2. Vai tr dopamin trong vic to hnh vi cm xc khi s dng ma ty

Trong cc cht dn truyn thn kinh, DA c lin quan nhiu nht n c ch to

phn thng hay cn gi l hnh vi cm xc (hng phn, sng khoi) sau khi s

dng cht ma ty. Ngoi ra, DA cn lin quan n c c ch ph thuc vo cc cht

ma ty hay cn gi l nghin thuc. Nghin l mt bnh l thn kinh khi m vic

-8-

lm dng cc cht gy nghin s gy hi cho h thng phn thng v nh hng

n hnh vi cm xc bnh thng ca no [4]. Khi s dng cc cht ma ty nh

cocain hay amphetamin, ngi s dng s tri nghim vic tng mnh DA trong

no, gy ra cm gic "phn thng"[19]. Vo nhng nm 80, cc nghin cu thm

tch micro (microdialysis) cho thy phn ln thuc gy nghin lm tng nng

DA vng th vn (striatum), vng v no (cortex) hay vng nhn accumben

(nucleus accumbens) [109], c bit l vng nhn accumben [77] (Hnh 1.4).

Hnh 1.4. Cc con ng dn truyn phn thng trong no khi s dng mt s

cht in hnh nh: Opioid, Ethanol, Barbiturat, Amphetamin, Cocain, Cannabioid,

Phencyclidin cho thy dn truyn dopamin tp trung ch yu vng nhn

accumben

Xt v c tnh th th tc dng (receptor), cc bng chng khoa hc ch ra

rng th th D1 khuyn khch vic c th tng cng s dng cc thuc kch thch,

trong khi th th D2 c vai tr iu ho qu trnh c th b kch thch do thuc [96]. Ni cch khc, kch thch th th D1 s lm tng nhu cu s dng thuc ca con

ngi v ngc li, kch thch th th D2 s lm gim nhu cu s dng thuc [96]. Do

, nhiu ti nghin cu cc cht i khng th th D1 nh mt liu php iu tr

cai nghin mi cho cc trng hp nghin ma ty.

-9-

Tuy cc cht ma tu u lm tng nng DA v to ra phn thng, nhng

c ch ca mi cht ma tu l khc nhau. Hiu r c ch tc dng phn t ca tng

nhm cht ma tu l mt yu t quan trng trong vic nghin cu v pht trin cc

loi thuc cai nghin.

Amphetamin

Khi s dng Amphetamin, nng DA trong no tng ln theo 3 con ng:

1) Amphetamin gn vo mng synap trc ca cc t bo thn kinh dopaminergic

v tng cng gii phng DA ti cc tn cng. 2) Amphetamin tng tc vi cc

bc nh cha DA lm cc bc ny tng cng gii phng DA. 3) Amphetamin gn

vi cc knh vn chuyn thu hi DA trn mng synap trc v lm o ngc c

ch vn hnh ca cc knh ny,

ngha l khin chng nh DA thay

v ti hp thu [27] (Hnh 1.5). Do

nng DA khi s dng

Amphetamin s lm nng DA

tng ln gp hng chc ln so vi

khi s dng cocain hay cc cht

ma ty nhm opiat, t tc dng

mnh ln c ch phn thng

gy ra cc hnh vi hng phn,

kch thch, o gic v sng khoi.

Hnh 1.5. C ch lm tng gii phng DA trong no ca Amphetamin

Opiat

Opiat gn vi cc receptor c hiu , , [29, 40], trong receptor -opiat c

vai tr quan trng trong c ch "phn thng" v l ch tc dng chnh ca opiat.

Opiat s kch thch cc t bo thn kinh dopaminergic thng qua vic c ch t bo

thn kinh trung gian GABA c cha cc th th -opiat. y s l tn hiu kch

-10-

thch cc t bo thn kinh dopaminergic gii phng DA (Hnh 1.6) t gy ra cc

hnh vi cm xc nh hng phn, sng khoi.

Hnh 1.6. C ch kch thch gii phng DA ca opiat

Cocain

C ch gy nghin ca Cocain l ngn chn s ti thu hi DA ca cc knh vn

chuyn thu hi DA (DAT, dopamine transporter) mng synap trc [144]. Cocain

s phong b cc knh vn chuyn ny lm cho DA khng c thu hi tr li synap

trc, dn n nng DA tng cao trong dch ngoi bo, v gn vi cc th th

DA synap sau (Hnh 1.7).

Hnh 1.7. C ch gii phng DA v to hnh vi cm xc sau khi s dng

cocain

-11-

1.2. MA TY V TC DNG CA MA TY

1.2.1. Khi nim v ma ty

Ngha Hn Vit ca ma tu

Ma ty l t Hn Vit, vi ngha: ma l t m, ty l say sa. Nh vy, ma

ty l cht a n s say sa, m mn. y cng l t ting Vit dng dch ch

nc ngoi khi mun ni ti ch cc cht gy nghin thuc loi nguy him nht:

thuc phin, morphin, heroin, cocain, cn sa v mt s thuc tng hp c tc dng

tng t morphin c s dng trong iu tr y t. Nh vy, c th gi nm na: ma

ty l cht a n s say sa v m mn, hay ni cch khc: ma ty l cht gy

nghin.

Khi nim cht ma tu Vit Nam v trn th gii

Trn th gii cha c nh ngha chnh thc v ma tu m thay vo l cc

danh mc cht ma tu. Cng c thng nht v cc cht ma ty nm 1961 [6] v

Cng c v cc cht hng thn nm 1971 [5] u lit k thnh 4 danh mc. Vit

Nam, t nm 1997, Vit Nam tham gia cc Cng c quc t ca Lin Hip

Quc v kim sot ma ty; t cm t ma tu c s dng ph bin nc ta

v xut hin rng ri trong cc vn bn php lut nh Lut phng chng ma tu.

Theo khon 1 iu 2 Lut Phng chng ma tu (nm 2000) th Cht ma tu bao

gm cht gy nghin v cht hng thn c quy nh trong cc danh mc do

Chnh ph ban hnh. Trong , cht gy nghin l cht kch thch hoc c ch

thn kinh, d gy tnh trng nghin i vi ngi s dng, v theo khon 2 v

khon 3, iu 2 lut Phng chng ma tu nm 2000 th cht hng thn l cht

kch thch, c ch thn kinh hoc gy o gic, nu s dng nhiu ln c th dn ti

tnh trng nghin i vi ngi s dng [1] .

Trn th trng cc loi ma ty tn ti di nhiu hnh dng v mu sc khc

nhau (Hnh 1.8).

-12-

Hnh 1.8. Mt s hnh dng ca cc vin ma ty trn th trng

Nh vy cc cht gy ra tnh trng nghin bao gm cc cht ma ty hay cc

cht gy nghin v cc cht hng thn, thng thng chng c gi chung l ma

ty.

1.2.2. Phn loi cc cht ma ty

C nhiu cch phn loi cc cht ma tu, gm c : phn loi theo lut php,

phn loi theo tc dng, phn loi theo ngun gc sn sinh. Trong chng ta s

dng nhiu nht l phn loi theo tc dng v phn loi theo ngun gc sn sinh ca

cht ma tu.

1.2.2.1. Phn loi theo tc dng ca cht ma tu [75]

Danh mc phn loi theo DRE (Drug Recognition Expert) ca M [75] chia ma

tu thnh 7 nhm chnh theo triu chng v tc dng ca chng trn c th:

c ch thn kinh (CNS Depressants): ru, thuc an thn, Barbiturat...

Kch thch thn kinh (CNS Stimulants): Cocain, Metamphetamin, Cafein

Cht gy o gic (Hallucinogens): Peyote, Psilocybin, ht ging rau mung,

cc cht tng hp nh Acid lysergic (LSD) v Ectasy (MDMA)

Phencyclidin (PCP) v cht tng t.

-13-

Cht gim au thuc nhm ma tu (Narcotic Analgesics): Heroin, Morphin,

Codein, Oxycondin, Vicodin, Percodan, Fentanyl, Dilaudid, Demerol

Cht xng ht (Inhalants): gasoline, N2O (kh ci), amyl nitrit, ether

Cannabis: cn sa.

1.2.2.2. Phn loi theo ngun gc sn sinh ca cht ma tu

Da theo ngun gc sn sinh, cc cht ma tu c th c phn loi theo 3

nhm : t nhin, bn tng hp v tng hp [33]. Trong cc cht bn tng hp v

tng hp l cc cht rt nguy him, c th gy nh hng n kh nng nhn thc

v hnh vi ca con ngi.

T nhin

Cc cht ma tu c ngun gc t nhin bt ngun t thc vt v i hi t hoc

hu nh khng giai on ch bin. Opium (morphin), Cannabis (cn sa) v cao

Cca (cocain) thuc vo nhm ny.

Bn tng hp

Cc cht ma tu bn tng hp c to ra bng cch x l ho hc cc cht ma

tu t nhin. Vic x l ho hc ny c dng chit tch hot cht chnh hay

thay i cu trc ca chng. Heroin l v d in hnh ca nhm ny.

Tng hp

Cc thuc tng hp c sn xut hon ton thng qua cc quy trnh ho hc,

bao gm cc cht nh Methaqualon (Mandrax), Amphetamin, Diazepam, Ecstasy

v.v

1.2.3. Tc dng ca ma ty

Ma ty xut hin t lu v chng ta c th thy c tc hi ca n n

khng ch bn thn ngi s dng m ton x hi. Ma ty to cm gic hng phn,

sng khoi, d chu sau khi s dng [22, 123]. Ngi dng c cm gic lng lng, hnh

phc. S hng phn, sung mn, t tin ca nhng ngi s dng ma ty khin h c

th lm nhng iu h khng dm khi cn tnh to. C th thy mt im chung

-14-

gia DA v ma ty l cm gic sng khoi d chu v trn thc t nhiu th nghim

c tin hnh chng minh mi lin quan ny.

1.3. NGHA KHOA HC LIN H GIA DOPAMIN V CHT MA TY

1.3.1. Nghin cu c ch tc dng phn t ca cc cht ma ty v c ch cai

nghin ca cc thuc mi.

Hin nay c rt nhiu loi thuc gy nghin. Mt s c s dng iu tr

trong y hc, s khc b lm dng dn n tnh trng nghin, in hnh nh cocain,

nicotin hay amphetamin v cc dn cht ca n. Tuy nhin, phn ln cc cht ma

ty hin nay vn cha lm sng t c c ch tc dng phn t, c bit l cc loi

ma ty tng hp mi. Vic khng nh mi lin h gia dopamin (DA) v cc cht

ma ty ny s gip ch cho cc nh nghin cu t tin hn, c bng chng hn trong

vic khm ph cc nghin cu v c ch tc dng phn t ca cc cht ma ty, t

lm c s cho cc nghin cu tm ra c ch cai nghin cho mi cht ma ty.

Rt nhiu nghin cu trn ngi chng minh s lin quan gia cc cht ma

ty lm tng nng DA trong no ngi [140, 141, 144]. Tuy nhin vic nh lng

trc tip nng DA trong no ngi lm mc ch nghin cu u khng thc

hin c v tnh an ton cho ngi th nghim. Thay vo l phng php

nghin cu gin tip thng qua o mt th th DA (D1 hoc D2) v knh vn

chuyn thu hi DA (DAT, Dopamin Transporter) da vo k thut chp ct lp

pht x positron (PET). PET l mt k thut hnh nh c s dng o nng

cht pht x trong m sng (Hnh 1.9). Cc nguyn t pht x t nhin thng

c s dng l 11C, 15O, 13N, 18F. Cc cht ny s gn vi cht ma ty, v d nh 11C-cocain. Phc hp s n gn kt vi th th DA (D1 hoc D2) v knh vn

chuyn ti thu hi DA (DAT), sau chp nh ct lp pht x positron (PET)

nhn bit mc phc hp ny khi gn kt, trn c s c th nh gi hiu qu

tc dng ca thuc trn nng DA [144].

-15-

Hnh 1.9. S khe synap DA v

hnh nh chp PET cc m ch

khc nhau: Knh vn chuyn thu

hi DA chp vi 11C D-threo

methylphenidat v th th D2 chp

vi 11C raclopride [143].

Knh vn chuyn thu hi DA (Dopamine transporter hay DAT) c bn cht l

mt protein mng synap trc ca t bo thn kinh dopaminergic. DAT c vai tr

vn chuyn thu hi DA c gii phng vo khe synap quay tr li cc tn cng

t bo synap trc. Bng cch phong b DAT, thuc s lm tng nng DA ti

synap v tng tc dng ca DA trn cc th th ca DA. V d nh trn ngi s

dng methylphenidat ng ung, c 60% DAT b phong b th lm tng nng

DA vng th vn ln khong 168% [145]. Mc chim gi DAT ca cc thuc

mi liu khc nhau khng ging nhau (Bng 1.2).

Bng 1.2. nh hng ca cc thuc n mc phong b DAT trn ngi

Thuc Liu dng ng dng Mc chim

gi DAT TLTK

Cocain

0.05 mg/kg i.v. 41 3% [144]

0.05 mg/kg i.v. 40% [141]

0.1 mg/kg i.v. 47 10% [144]

0.13 mg/kg i.v. 50% [141]

-16-

0.3 mg/kg i.v. >60% [141]

0.3 mg/kg i.v. 60 10% [144]

0.6 mg/kg i.v. 77 10% [144]

0.6 mg/kg i.v. >60% [141]

Methylphenidat

0.025 mg/kg i.v. 35 5% [144]

0.1 mg/kg i.v. 62 13% [144]

0.1 mg/kg i.v. 60% [141]

0.25 mg/kg i.v. 67 3% [144]

0.375 mg/kg i.v. 80-84 7% [140]

0.5 mg/kg i.v. 78 11 % [144]

0.75 mg/kg i.v. 50% [141]

Hn na, vic nh lng chnh xc nng DA c tin hnh qua cc th

nghim cn lm sng [68, 108]. Trong nhng nm gn y, phng php thm tch

micro (microdialysis) c p dng ngy cng ph bin [79] o nng DA trong

no chut thc nghim sau khi c tim thuc c bn cht l ma ty (nh

morphin, amphetamin, cocain) [135]. T hnh thnh nn cc nghin cu c bn v

c ch tc dng mc phn t ca mi cht ma ty.

1.3.2. Nghin cu phng php thm nh hiu qu tc dng ca cc cht ma

ty

Hin nay, vi din bin phc tp ca ti phm ma tu, cc loi ma tu tng hp

mi c ra i vi cu trc v thnh phn a dng, khin cho vic pht hin v

qun l ma tu tr nn rt kh khn. Cc loi phn ng test nhanh (screening test)

nc tiu, mu hay dch sinh hc khc trn th trng tuy ph bin v tin dng,

nhng c nhiu hn ch nh l ch pht hin c 5 nhm ma tu ph bin vi

nhy thp, rt d b lm gi nh pha long hay tro mu, d xy ra phn ng cho

-17-

gy kt qu dng tnh sai [156]. Nhc im ln nht ca cc phng php xt

nghim xc nh trong phng th nghim l phi thay ct nhiu ln, th cc pha

ng khc nhau v mi ct ch dnh cho mt cht ma tu nht nh v nu pha ng

khc nhau th thi gian lu cng khc nhau, kh c th so snh c. iu ny gy

kh khn cho hot ng phng chng ma tu, khi m tnh hnh ang tr nn phc

tp hn, c bit khi cc cht ma ty di dng tng hp mi, c cu trc mi kh

c th c cht chun xc nh. Mt khc, khi thu c mt mu bt trng, mun

bit chng c phi ma tu hay khng s phi tri qua rt nhiu phn ng th nghim

xc nh. Nh vy, thng qua vic khng nh mi lin h khi s dng cc cht

ma ty vi DA, chng ta c th xy dng 1 phng php mi nhm thm nh li

c phi l ma ty hay khng thng qua vic o nng DA trn no chut thc

nghim da vo k thut thm tch micro (Microdialysis). K thut ny cho php

chng ta nh gi tc dng kch thch ca bt k cht ma ty no vi nguyn tc

n gin hn rt nhiu.

Di y l m hnh thm nh ma ty nhanh bng k thut thm tch micro

(Hnh 1.10).

Hnh 1.10. S thm nh cc cht ma ty nhanh bng k thut thm tch micro online [137].

1. H thng bm tim 2. B phn chnh dng 3. Thit b thu mu 4. Kim thm d 5. Dng c cha ng

vt thc nghim di chuyn t do 6. Bn 7. Van tim 8. Ct HPLC 9. Bm pha ng 10. Pha ng

11. Detector 12. My tnh

-18-

Phng php thm tch micro (Microdialysis) trong nghin cu nh

lng dopamin trong no

Trc gi thuyt v vic s dng cc cht gy nghin (cc cht ma ty t nhin

nh morphin, cocain, cht bn tng hp nh heroin hay ma ty tng hp nh

amphetamin) lm tng nng DA trong no (c th hn l cc vng nhn

accumben, th vn v VTA), nhiu th nghim tin lm sng trn chut c tin

hnh ti nhiu ni trn th gii vi s h tr ca k thut thm tch micro

(microdialysis).

Thm tch micro l 1 k thut cho php xc nh c nng cc cht ni

sinh (v d: cc cht dn chuyn thn kinh nh serotonin, noradrenalin, dopamin) v

cc cht ngoi sinh (phn t thuc) ti m ch tc dng ca thuc, da vo s

khuch tn th ng theo gradient nng ca cc phn t c trng lng thp khi

qua l ca 1 mng bn thm trn 1 kim thm d c cy vo t chc ch.

Mt quy trnh cho th nghim vi phng php thm tch micro th cn tri qua

cc bc sau [2]:

Bc 1: Chun b nguyn liu: kim thm d, dch truyn c thnh phn v nng

tng ng vi dch ti m ch cn nghin cu v i tng nghin cu (chut,

th, mo hoc ngi tham gia nghin cu).

Bc 2: Cy kim thm d vo m ch nghin cu.

Bc 3: Truyn dch c thnh phn v nng tng ng vi dch ti m ch

vi tc rt chm (1-2l/pht), dch thu c s cha cc phn t cn nghin cu.

Bc 4: nh lng nng phn t cht cn nghin cu bng phng php

thch hp. V nng ny rt thp v th tch dch em i phn tch nh nn thng

s dng phng php nh sc k lng hiu nng cao (HPLC) c detector hunh

quang hay in ha hoc phng php sc k lng khi ph (LC-MS).

Bc 5: Hiu chnh li nng thuc thng qua hiu sut in vitro hoc in vivo

ca mng bn thm, nu trong cc nghin cu nh lng nng cc cht ni sinh

th khng cn phi hiu chnh li hiu sut mng bn thm ny.

-19-

y, cc th nghim c chng ti la chn nghin cu v cht ni sinh DA,

kim thm d s c cy vo vng nhn accumben, vng th vn hay VTA thuc

vng no ca chut thc nghim (Hnh 1.11)

Hnh 1.11. S m t s dng k thut thm tch micro c cy

trong cc vng no VTA (trung tm sinh ra DA) v vng nhn

Accumben (ni gii phng DA, gy ra phn thng).

Trong no chut, v tr vng cy kim thm d c xc nh tnh t mng cng

ca v no v v tr im thp (bregma) trn mng cng (Hnh 1.12).

Hnh 1.12. Hp s ca chut nhn t trn xung

-20-

Xut pht t im thp bregma kim thm d s c dch chuyn tin trc

sau, sang tri phi so vi im thp bregma v sau c m su xuyn qua

mng cng vo no theo v tr ta c nghin cu trong bng 1.3.

Bng 1.3. Ta cy kim thm d ti cc vng no

Vng no Ta cy kim thm d t v tr im thp (mm)

TLTK Tin li (A) Tri phi (L) Ln xung (V)

Nhn accumben +1.2 1.0 -5.0 [46]

Th vn +1.2 1.5 -3.0 [46]

VTA -6.7 0.6 -8.0 [124]

-21-

CHNG 2: TNG QUAN H THNG V HIU QU CA

MORPHIN/AMPHETAMIN TRN NNG DOPAMIN

TRONG NO CHUT THC NGHIM

2.1. GII THIU CHUNG

Dopamin (DA) v ma ty c bit n t lu vi cng mt vai tr lin quan

n hnh vi cm xc, mang li cm gic hng phn, sng khoi v d chu cho con

ngi [9, 22, 28, 123]. Cho n nay, c rt nhiu nghin cu c tin hnh lm

sng t v mi lin h tng nng DA trong no sau khi s dng cc cht ma ty.

Tuy nhin ch l cc nghin cu n l, m cha c mt nghin cu tng quan h

thng (systematic review) no c thc hin cung cp bng chng khoa hc

cao hn. Trn c s , chng ti thc hin nghin cu ny nhm a ra ci nhn

ton din v khch quan v mi lin h ca DA vi cc cht ma ty.

Hnh 2.1. Mi lin h gia dopamin trong no, cc cht ma ty v hnh vi cm gic

Trong phm vi nghin cu ny, chng ti cng ch tp trung n vng ventral

tegmental (VTA) l trung tm chnh ca cc con ng truyn DA; vng nhn

accumben v vng th vn (striatum) l hai im ch cui cng ca con ng vn

[9, 28] [22, 123]

-22-

chuyn gii phng DA, gy ra c ch phn thng trn ng vt c v v tng

quan trn 2 thuc c th l morphin (mt cht ma ty c ngun gc t nhin) v

amphetamin (mt cht ma ty c ngun gc tng hp).

2.2. I TNG V PHNG PHP NGHIN CU

2.2.1. i tng nghin cu:

2.2.1.1. Cc ngun c s d liu

Cc y vn nghin cu l cc bi bo nghin cu c tm kim trn cc ngun

d liu: Pubmed v cc tp ch nghin cu v Y Dc hc Vit Nam (Tp ch Dc

hc, Tp ch nghin cu Dc v thng tin thuc, Tp ch Y hc thc hnh). La

chn cc bi bo c tnh n ht ngy 01/03/2013.

2.2.1.2. Tiu chun la chn cc bi bo

La chn cc bi bo c cc tiu chun sau:

- Th nghim c tin hnh trn chut bnh thng (wide type).

- Thuc c s dng cho th nghim : amphetamin (v cc tn gi ng

ngha khc c tra cu trong MeSH) v/hoc morphin (v cc tn gi ng

ngha khc c tra cu trong MeSH).

Hnh 2.2. Cng c MeSH tm kim t ng ngha

- Thuc c s dng ng tim di da hoc tim mng bng.

- Cc thuc c s dng iu tr cp tnh.

-23-

- S dng phng php thm tch micro (microdialysis).

- Nhm s dng thuc c so snh vi nhm khng s dng thuc.

- Nghin cu a ra kt qu so snh nng DA trong no ti vng Nhn

Accumben (Nucleus accumbens) v/hoc vng th vn (Striatum) v/hoc

vng Ventral tegmental (ventral tegmental area) nhm chut dng thuc so

vi nhm chut khng dng thuc. Kt qu l t l phn trm nng DA (%)

ti cc vng trong no ca nhm s dng thuc so vi nhm chng.

2.2.1.3. Tiu chun loi tr

Loi tr cc bi bo c 1 trong cc tiu chun sau:

- Nghin cu tin hnh trn cc chut c gy m hnh bnh, chut bin i

gen, chut ci, chut s sinh.

- Thuc c tim trc tip vo no.

- Thuc s dng mn tnh.

- Cc bi bo tng quan.

2.2.2. Phng php nghin cu:

2.2.2.1. Chin lc tm kim

Tm kim trn cc tp ch Y Dc hc Vit Nam (tp ch Y hc thc hnh,

tp ch Dc hc, tp ch nghin cu Dc v thng tin thuc): Tm kim

bng tay cc bi bo c cng b trn tp ch tnh n ngy 01/03/2013.

Kt qu 01 bi nghin cu c tm thy ng trn Tp ch Dc hc.

Tm kim trn Pubmed/Medline: http://www.ncbi.nlm.nih.gov/pubmed/

- Tm kim cc t ng ngha ca cc t kha: Morphine, Amphetamine,

Ventral tegmental, Nucleus accumbens, Striatum, Microdialysis, Dopamine

trn trng MESH ca MEDLINE.

- Ngy tm kim: 01/03/2013

- Dng cc ton t OR v AND to thnh cu lnh sau:

-24-

Kt qu thu c tnh n ngy 01/03/2013 l: 829 bi bo nghin cu.

2.2.2.2. Quy trnh tm kim v la chn bi bo

Cc bi bo sau khi c tm kim trn cc ngun c s d liu s c

nh gi theo cc tiu chun la chn v tiu chun loi tr c nu trn.

Qu trnh ny c tin hnh qua cc bc (Hnh 2.3):

Bc 1: La chn bi bo qua tiu v tm tt (abstract). Mt s bi bo s

c loi b nu ni dung tiu v abstract khng ph hp vi tiu chun

la chn hoc c nhng tiu chun loi tr.

Bc 2: Cc bi bo c la chn qua bc 1 s c la chn ln 2 bng

cch c ni dung chi tit bi bo (fulltext) v nh gi da trn tiu chun la

chn v tiu chun loi tr.

Bc 3: Cc bi bo c la chn sau bc 2 s chnh thc c a vo

phn tch kt qu.

((Morphia OR Morphine OR SDZ 202-250 OR SDZ 202 250 OR SDZ

202250 OR SDZ202-250 OR SDZ202 250 OR SDZ202250 OR MS

Contin OR Oramorph SR OR Duramorph)

OR

(Phenopromin OR Phenamine OR Amfetamine OR Desoxynorephedrin OR

Fenamine OR Centramina OR Mydrial OR Thyramine OR Amphetamine OR

l-Amphetamine OR Levoamphetamine OR levo-Amphetamine))

AND

(ventral tegmental OR nucleus accumbens OR (Corpus Striatum OR

Lenticular Nucleus OR Nucleus Lentiformis OR Lentiform Nucleus))

AND

microdialysis

AND

(dopamine OR 3,4-Dihydroxyphenethylamine OR 3,4

Dihydroxyphenethylamine OR 4-(2-Aminoethyl)-1,2-benzenediol OR

Intropin)

-25-

Trong trng hp khng ly c bi c fulltext, cc bi bo s c nh

gi da trn ni dung tiu v tm tt (abstract). Bi bo ch c la chn nu

ni dung tm tt tha mn cc tiu chun nh gi v c kt qu c th.

Nh vy, cc bi bo sau khi c tm kim trn cc c s d liu s c

nh gi da vo tiu , tm tt v ni dung chi tit theo cc tiu ch c nu

ra t trc. Vic la chn cc bi bo qua tng bc u c s trao i v ng

thun gia ngi lm nghin cu v Thy hng dn.

Quy trnh tm kim v thu thp bi bo c trnh by trong hnh di y

(Hnh 2.3).

Hnh 2.3. S quy trnh tm kim v la chn bi bo

Cc bi bo c tiu

v abstract ph hp

nhng khng ly c

fulltext

Tm kim bi bo nghin cu trn Pubmed v cc tp ch

Y Dc hc Vit Nam

La chn cc bi bo t tiu chun phn tch kt qu

nh gi cc bi bo qua

c fulltext

Loi tr cc bi bo

khng t tiu chun

nh gi cc bi bo qua

c tiu v tm tt

Loi tr cc bi bo

khng t tiu chun

-26-

2.2.2.3. Ni dung thu thp t bi bo c la chn

Bng chit xut d liu s tng kt thng tin theo tn tc gi; nm xut bn bi

bo; c im ca chut lm nghin cu: loi, cn nng, s lng trong tng nhm;

v tr cy kim thm d; thuc c la chn nghin cu; liu; ng dng v kt

qu phn trm mc tng nng DA sau khi tim thuc so vi nng nn trc

khi tim.

2.2.2.4. X l s liu

Trong qu trnh lm tng quan h thng (systematic review), tt c cc bi bo

nghin cu, kt qu x l s liu sau qu trnh tm kim c lu tr v qun l

bng phn mm Endnote X5.0.1.

-27-

2.3. KT QU NGHIN CU

2.3.1. S lng nghin cu cn phn tch h thng

Sau khi tm kim trn cc ngun c s d liu, chng ti tm c 830 bi bo,

trong c 829 bi trn ngun c s d liu Pubmed v 1 bi trn Tp ch Dc

hc. Kho st trn tiu v tm tt (abstract) ca 830 bi, chng ti la chn 106

bi tha mn tiu chun. Trong 106 bi c 5 bi khng ly c ni dung chi tit

(fulltext). Tuy nhin, sau khi c ni dung 5 bi abstract trn khng thu c s liu

kt qu nn b loi (Danh sch bi bo b loi xem Ph lc 2). Sau khi c cn

thn ni dung chi tit ca 101 bi bo ly c fulltext, c 18 bi bo c la chn

cui cng v 83 bi bo b loi v cc l do (xem ph lc 1):

- Chut khng t yu cu (n=11)

- S dng thuc Molsidomin hoc Nitroindazol trc khi tim amphetamin (n=1)

- Thuc c s dng mn tnh (n=2)

- Nghin cu c mc ch khc v khng ly c s liu (n=14)

- Th nghim khng s dng amphetamin hoc morphin (n=4)

- Th nghim khng s dng phng php thm tch micro (n=1)

- Khng c s liu mc tng DA (n=20)

- Th nghim khng c nhm chng (n=12)

- Khng s dng ng tim di da hoc tim mng bng (n=11)

- Vng cy kim thm d khng nm trong vng nghin cu (n=7)

Trong 18 bi c la chn cui cng, chng ti s phn tch kt qu da trn 3

tiu ch:

- Hiu qu ca amphetamin trn s thay i nng DA trong no (n=9)

- Hiu qu ca morphin trn s thay i nng DA trong no (n=7)

- So snh hiu qu ca amphetamin vi morphin trn s thay i nng DA

trong no (n=2).

Kt qu v s lng bi c la chn hay loi tr c tm tt trong s

di y (Hnh 2.4). n l s bi bo nghin cu.

-28-

Hnh 2.4. Kt qu la chn bi bo

83 bi bo b loi v cc l do: - Chut khng t yu cu (n=11) - S dng thuc Molsidomin hoc

Nitroindazol trc khi tim amphetamin (n=1)

- Thuc c s dng mn tnh (n=2) - Nghin cu c mc ch khc (n=14) - Th nghim khng s dng amphetamin

hoc morphin (n=4) - Th nghim khng s dng phng php

thm tch micro (n=1) - Khng c s liu mc tng DA (n=20) - Th nghim khng c nhm chng (n=12) - Khng s dng ng tim di da hoc

tim mng bng (n=11) - Vng cy kim thm d khng nm trong

vng nghin cu (n=7)

La chn phn tch: n=18 Loi: n=83 (Ph lc 1)

Amphetamin v morphin: n=2

Amphetamin: 9

Morphin: n=7

Cc y vn nghin cu C s d liu: Pubmed (829 bi), Tp ch Dc hc (1 bi). Gii hn: nghin cu trn cc bi bo c cng b t ngy 01/03/2013 tr v trc

Bi bo c nh gi trn tiu v abstract

Tng s bi bo nghin cu tm kim c: n=830 bi

Cc bi bo b loi tr: n=724 vi cc l do: - Khng s dng thuc ang nghin cu: n=300 - Khng nghin cu v dopamin:n= 98 - L bi tng quan: n=8 - Khng nghin cu trn chut: n=13 - Nghin cu s dng mn tnh thuc morphin v/hoc

amphetamin: n=72 - Chut khng tha mn yu cu : n=88 - Nghin cu vng no khc: n=40 - ng s dng thuc khng phi l i.p. hay s.c.: n= 43 - Thit k nhm nghin cu khng ph hp (Thuc khc

c s dng trc morphin hoc amphetamin; khng c nhm i chng khng dng thuc): n=46

- Mc ch nghin cu tc dng ca mi trng n tc dng ca thuc: n=3

- Khng s dng phng php thm tch micro: n=13

S bi bo ly c fulltext: n=101

S bi bo thu c sau khi c tiu v abstract: n=106

S bi bo khng ly c fulltext: n=5 Loi v khng c kt qu c th (Ph lc 2)

-29-

2.3.2. Hiu qu ca amphetamin trn s thay i nng dopamin trong no

Trong s 18 bi nghin cu c la chn a vo phn tch, c 9 bi bo c

ni dung nghin cu v thuc amphetamin.

Th nghim tin hnh trn chut cng loi Wistar:

1. Kurling-Kailanto, S. v cng s 2010 [85]: Mc tiu ca nghin cu l phong

b th th androgen hay estrogen lm gim kh nng tc dng ca nandrolon trong

vic thay i tc dng cp tnh ca amphetamin trn nng DA trong no chut.

Chut c (300-350g) c chia lm 2 nhm, trong nhm chng (n=6) c

tim NaCl 0.9% v nhm th nghim (n=6) c tim mng bng amphetamin

1.0mg/kg. Kt qu l amphetamin lm tng nng DA ngoi bo vng nhn

accumben ln 1100% so vi nng nn (s khc bit c ngha thng k so vi

nhm chng, p

-30-

ln n 700%, 800% v 1300% (tng ng vi liu 1.0, 3.0 v 9.0mg/kg) so vi

nng nn (Bng 2.1).

4. Butcher, S. P. v cng s 1988 [19]: Mc tiu ca nghin cu l s tng gii

phng DA do amphetamin vng th vn trn chut c, c cn nng trong khong

250-300g. Cc nhm th (n=4) c tim mng bng amphetamin vi cc liu 2.0,

4.0, 8.0 v 16.0mg/kg. Nhm chng (n=4) c tim NaCl 0.9%. Kt qu cho thy

nng DA nhm th nghim sau khi tim thuc tng ln so vi nng nn,

tng ng vi liu trn l 350%, 720%, 1100% v 1400% (Bng 2.1).

Th nghim tin hnh trn chut cng loi Sprague Dawley:

5. Rowley, H. L. v cng s 2012 [119]: Nghin cu c tin hnh trn chut

c (250-350g). Kim thm d c cy vng th vn. Nhm th (n=5-6) c

tim mng bng amphetamin 1.5 mg/kg lm tng nng DA vng th vn rt

nhanh v t mc ti a sau 30 pht l 1291522% so vi nng nn (s khc

bit c ngha thng k vi nhm khng dng thuc (n=5-6), p

-31-

DA trong no tng ln 650% so vi nng nn ngay lp tc (s khc bit c

ngha thng k so vi nhm chut c tim NaCl 0.9%, p

-32-

Bng 2.1. Kt qu cc nghin cu v s thay i nng DA trong no

khi s dng amphetamin trn chut cng.

Th t

Tn tc gi, nm xut

bn

Loi chut cng

Cn nng (g) n

V tr o DA

ng dng

Liu mg/kg

Mc tng t l % nng DA so vi nng

nn

1 Kurling-

Kailanto, S. 2010 [85]

Wistar 300 350 6

NAc: A=+1.9 L=1.0 V=6.0

i.p. 1.0 1100%

2 Afanas'ev, II 2001 [7] Wistar 250300 10

Th vn: A=+0.5 L= +3 V= -7.0

i.p. 5.0 950450%

3 Kankaanpaa, A. 1998 [76] Wistar chut t

11 n 12 tun tui

5-6

NAc: A=+2.0 L=-1.2 V=-8.0

s.c. 1.0 700%

3.0 800%

9.0 1300%

4 Butcher, S. P. 1988 [19] Wistar 250-300 4

Th vn: A=+0.5 L=2.5 V=7

i.p.

2.0 350% 4.0 720% 8.0 1100%

16.0 1400%

5 Rowley, H. L. 2012 [119] Sprague Dawley 250-350 5-6

Th vn: A=+0.2 L=+3.0 V=-7.8

i.p. 1.5 1291522%

6 Auclair, A. L.2010 [11] Sprague Dawley 330380 4-6

Th vn: A=9.8 L=3.3 V=2.7

i.p. 0.5 324%

7 Dawson, L. A. 2003 [31] Sprague Dawley 280350 8-12

Th vn: A=+0.2 L=3 V=3

s.c. 0.3 311.3 73.5%

8 Hurd, Y. L. 1992 [68] Sprague Dawley 250-300 5-6

NAc: A=+1.7 L=+1.3 V=-7.3

s.c. 1.5 650%

9 Sharp, T. 1987 [125] Sprague Dawley 280-320 9

NAc: A=+3.2 L= +1.5 V=-7.7 Th vn: A=+2.2 L=+2.5 V=-6.0

s.c.

0.5 NAc: 642% Th vn: 608%

2.0 NAc: 1236% Th vn 1629%

5.0 NAc: 3568% Th vn: 2291%

n: s chut/nhm i.p.: tim mng bng s.c.: tim di da

-33-

2.3.3. Hiu qu ca morphin trn s thay i nng dopamin trong no

C 7 bi bo nghin cu v nh hng ca morphin n nng DA trong no

trn chut cng c v chut nht c.

Th nghim nghin cu trn chut cng loi Sprague Dawley:

1. Basaran, N. F. v cng s 2010 [13]: Mc ch ca th nghim l nghin cu

glycyl-glutamin c ch tc dng lm tng nng DA ca morphin ti vng nhn

accumben. Trong nghin cu, chut c (250-350g) c s dng cho nghin cu.

Morphin liu 2.5 mg/kg tim mng bng lm tng nng DA ti vng nhn

accumben ln khong 600% so vi nng nn (s khc bit c ngha thng k

so vi nhm s dng dung dch NaCl 0.9%, p

-34-

5. Pothos, E. v cng s 1991 [109]: Bi bo cng nghin cu v s dng k

thut thm tch micro trong nh lng nng DA vng nhn accumben sau khi

s dng cp tnh morphin ng tim mng bng trn chut cng (320-375g). So

vi nhm chng s dng NaCl 0.9% (n=6) th nng DA nhm th (n=8) tng

ln ng k 195.6 62.26% (p

-35-


khi s dng morphin trn chut cng v chut nht

Th t

Tn tc gi u,

nm xut bn

Loi chut

Cn nng (g) n

V tr o DA

ng dng

Liu mg/kg

Mc tng t l %

nng DA so vi nng

nn

1 Basaran, N. F. 2010 [13]

Sprague Dawley 250350

Nhm chng: 5 Nhm th: 9

NAc A=0.9 L=1.8 V=7.5

i.p. 2.5 600%

2 Bland, S. T. 2004[16]

Harlan Sprague Dawley

250-350 6-8

NAc: A=-1.7 L=0.8 V=-6.0

s.c. 3 150%

3 Fadda, P. 2003 [47] Sprague Dawley 200-225 5

NAc: A=+1.7 L=0.7 V=8.2

i.p. 5 300%

4 Rada, P. 1991 [112] Sprague Dawley 325-375


NAc: A=10.0 L=1.2 V=4.0

i.p. 20 155%

5 Pothos, E. 1991[109]

Sprague Dawley 320-375


NAc: A=10 L=1.2 V=4

i.p. 20 195.61 62.26%

6 Enrico, P. 1997[42]

Wistar 265-300 Nhm chng: 5 Nhm th: 7

Th vn: A=+0.5 L=-2.5 V=-6.0

s.c 20 242%

7

Nguyn Thnh Hi. 2012 [3]

C57 20-25 3-6

NAc: A=+1.6 L=1.3 V=-5.0

s.c. 10 295%


-36-

2.3.4. So snh hiu qu ca amphetamin/morphin n s thay i nng DA trong no

Trong s 19 bi nghin cu c 02 bi bo c tin hnh nghin cu ng thi

trn hai thuc amphetamin v morphin.

1. Porras, G. v cng s 2002a [107]: Th nghim c tin hnh trn chut

cng c Sprague Dawley (330-380g). Mi nhm gm 4-6 con. Nhm chng c

tim dung dch NaCl 0.9%. Nhm th c tim di da morphin 2.5 mg/kg hoc

tim mng bng amphetamin 2.0 mg/kg. DA c o hai vng : th vn

(striatum) v nhn accumben. C morphin v amphetamin u lm tng ng k

nng DA so vi nhm chng (p

37


khi s dng morphin hoc amphetamin trn chut cng

Th t

Tn tc gi u,

nm xut bn

Loi chut

Cn nng (g) n

V tr o DA

ng dng

Liu mg/kg

Mc tng t l % nng DA so vi nng

nn

1 Porras, G. 2002a [107] Sprague Dawley 330380 4-6

NAc: A=11, L=1.3, V=2 Th vn: A=9.8, L=3.3, V=3

s.c. Morphin 2.5 NAc: 175% Th vn: 143%

i.p. AMPH 2 NAc: 2500% Th vn: 4300%

2 Porras, G. 2002b[108] Sprague Dawley 330380 4-9

NAc: A=11, L=1.3, V=2 Th vn: A=9.8, L=3.3, V=3

s.c. Morphin 2.5 NAc: 175% Th vn: 137%

i.p. AMPH 2 NAc: 2500%

Th vn: 4200%


38

2.4. BN LUN

2.4.1. c im chut lm th nghim

Chut c s dng cc th nghim ch yu thuc hai loi chut cng Wistar

v Sprague Dawle, vi c im kh tng ng v gii v cn nng (cn nng dao

ng t 200-380g). Cc nghin cu trn chut nht rt t, do khi lng chut rt

nh, no rt b nn vic thc hin nghin cu rt kh v phc tp. Trong kt qa h

thng ca chng ti thu c ch c nghin cu ca Nguyn v cng s (2012)

c nh gi trn chut nht c loi C57. y chng ti gii hn ch chn cng

mt ging chut c gim sai s gia cc nghin cu do yu t gii tnh gy ra.

Nh vy khi la chn ng vt th nghim t sai khc nhau s lm gim s khc

bit v yu t loi n kt qu ca cc nghin cu.

2.4.2. Liu v ng dng ca morphin v amphetamin

ng dng c la chn nghin cu l tim mng bng v tim di da.

Trong cc bi bo b loi, c nhng th nghim s dng thuc ng tim tnh mch

hay tim trc tip vo no. Nhng ng tim ny thuc s tc dng mt cch

nhanh chng v mnh n c th, c bit l ng tim trc tip vo t chc no.

Nng DA s tng ln nhanh chng v rt cao.

cc th nghim, c morphin v amphetamin u c dng c ng tim

di da v tim tnh mch. Liu dng ca c hai thuc tri rng t liu thp n liu

cao. Morphin ng tim di da v tim mng bng u c cc liu t 2.5 20

mg/kg [3, 13, 16, 42, 47, 109, 112]. i vi amphetamin cc liu ng tim mng bng t

0.5-16 mg/kg [7, 11, 19, 76, 85, 119] v liu tim di da 0.3-9 mg/kg [31, 68, 125].

2.4.3. nh hng ca morphin v amphetamin n nng ca dopamin trong no

Trong 18 bi bo nghin cu c chn phn tch, khng c nghin cu no

tin hnh trn vng Ventral tegmental (Ventral tegmental area, VTA). VTA l vng

39

khi ngun hay cn gi l trung tm xut pht ca cht dn truyn thn kinh DA.

C th nng DA VTA kh thp nn vic tin hnh o DA vng ny l kh t

i vi hai thuc morphin v amphetamin. Mt khc vng nhn accumben v vng

th vn (striatum) l mt trong nhng ni gii phng DA cui cng, do cha

ng lng DA gii phng nhiu hn v thch hp xc nh s thay i nng

DA khi s dng cc cht ma ty.

T 3 bng kt qu thu c trn (Bng 2.1; 2.2 v 2.3), chng ti thy: 100%

cc bi bo nghin cu c la chn phn tch h thng u a ra kt lun c

amphetamin v morphin u lm tng nng DA trong no vng nhn

accumben v vng th vn (striatum) tt c cc loi chut v tt c cc liu vi

ng tim mng bng hay ng tim di da. Mc tng nng DA thp

nht l 137% (ti vng nhn th vn) khi tim di da morphin 2.5 mg/kg chut

Sprague Dawley [108] v cao nht l 600% cng ti vng nhn accumben khi tim

mng bng morphin vi liu 2.5 mg/kg trn chut Sprague Dawley [13]. Khi s dng

amphetamin vi liu tng t 2 mg/kg n 16mg/kg c tim mng bng, nng

DA vng th vn tng tng ng t 350% n 1400%. Nu tim di da liu t

1-9 mg/kg th nng DA nhn accumben cng tng t 700% n 1300%. Xt

trn tng thuc vi cng ng dng v loi chut, nhn chung liu cng cao th

lng DA tng cng nhiu ti mi vng no kho st.

nh hng ca hai thuc morphin v amphetamin cng c s khc nhau. Trong

bng 2.3, hai nghin cu Porras, G. v cng s 2002a [107] v Porras, G. v cng s

2002b [108] u tin hnh trn c hai thuc. Chng ti thy vi liu gn nh nhau

morphin (2.5 mg/kg, s.c.) v amphetamin (2 mg/kg, i.p.) th mc tng DA gy ra

bi amphetamin cao hn rt nhiu (hn 10 ln) c hai vng no kho st. i vi

mi thuc cng c s khc bit v mc tng ti mi vng no nghin cu. ng

thi khi so snh cc nghin cu trn tng thuc nhn thy s khc bit v mc

tng DA do mi thuc gy ra. Morphin ch tng nh nng DA ln vi trm phn

trm k c liu cao, trong khi amphetamin c th tng nng DA ln vi nghn

phn trm. Nh vy amphetamin c tc dng mnh hn rt nhiu so vi morphin

40

hay nhm ma ty tng hp nh hng n DA trong no mnh hn so vi ma ty

c ngun gc t t nhin.

2.4.4. Hng pht trin trong tng lai

Hin nay mc tiu tm hiu c ch gy nghin ca cht ma ty rt c quan

tm. Kt qu thu c trong ti nghin cu ny cung cp bng chng lm

c s khoa hc cho cc nghin cu v c ch tc dng phn t ca cc cht ma ty.

Trong no, ngoi DA cn c rt nhiu cht dn truyn thn kinh khc nh GABA

(acid gamma-aminobutyric), noradrenalin hay seronin v chng u c mi lin h

mt thit vi nhau. Nn da trn tc dng lm tng nng DA trong no c

chng minh c th nghin cu nh hng cc cht ma ty cht dn tuyn thn kinh

khc thng qua mi lin h gia chng vi DA. V d nh cc nh nghin cu

tm ra ma ty tng hp ecstasy (tn khoa hc l 3,4-methylenedioxy-N-

methylamphetamine) c tc dng lm tng serotonin v dopamin [49]. Ecstacy tc

dng gin tip n h thng thng trong no. Serotoin tng ln s kch thch lm

tng nh gii phng DA trong no [58], thng qua c ch phn thng m ecstacy

c tc dng khi s dng. Vic hon thin y c ch phn t ca cc cht ma ty

rt c ngha trong qu trnh tm ra phng php cai nghin mi, gp phn khng

nh trong vic ci thin i sng cho bnh nhn nghin ma ty v ton x hi.

Mt khc tc dng lm tng nng DA trong no ca cc cht ma ty

c khng nh. y s l c s cho vic hnh thnh m hnh thm nh hiu qu

tc dng ca cc cht ma ty trong tng lai da vo cht trung gian l DA. Vi

mt mu cht trng nghi ng c cha ma ty, vic thm nh s dng phng php

thng thng i lc gp kh khn. Mt s l do khin cho vic thm nh mt

nhiu thi gian v khng chnh xc, nh mu thu c qu t hoc nng cht ma

ty trong mu rt thp hay mu c cha qu nhiu cht khin cho vic xc nh gp

nhiu sai s. Tuy nhin m hnh thm nh hiu qu tc dng ca cc cht ma ty s

dng phng php thm tch micro s hn ch c cc kh khn trn. Tin hnh

th nghim o nng DA trong no chut sau khi c tim cht trn c th gip

41

xc nh c phi l ma ty hay khng cho d mu thu c rt t hoc rt phc

tp. y s l hng i mi trong tng lai.

42

CHNG 3: KT LUN V KIN NGH

3.1. KT LUN

Dopamin (DA) l mt cht dn truyn thn kinh c cu trc n gin. N l sn

phm gii phng ra t cc t bo thn kinh dopaminergic. Mc d t bo thn kinh

dopaminergic chim t hn 1% tng s t bo thn kinh no nhng chng ng mt

vai tr v cng quan trng trong vic iu chnh mt s chc nng c bn ca no,

trong vai tr phn thng mang li cm gic hng phn, sng khoi kch thch

l mt v d in hnh. Thng qua cht dn truyn thn kinh DA, cc t bo thn

kinh dopamnergic m nhim cc chc nng cc vng no bao gm c hnh vi

vn ng, ng lc v ghi nh. c bit DA trc tip hoc gin tip tham gia vo

c ch gy nghin ca cc cht ma ty.

Cc cht ma ty (c th 2 cht ma ty c tng quan h thng: morphin v

amphetamin) u lm tng nng DA vng nhn accumben v vng th vn

(striatum) trn chut th nghim. Nghin cu cho thy d u lm tng nng DA

trong no nhng mc tng ti mi vng no, do mi thuc, vi mi liu gy ra l

khc nhau, ph thuc vo bn cht ca mi cht ma ty v liu lng ca mi cht

ma ty. Liu cng tng th nng DA tng cng ln. Amphetamin lm tng nng

DA mc thp nht khong 311% ti vng th vn liu 0.3mg/kg tim di da

v mc cao nht n 4300% ti vng th vn liu 2 mg/kg tim mng bng;

Morphin lm tng nng DA tt c cc liu: t 150% mc tng thp nht

liu 3 mg/kg tim di da n 600% mc tng cao nht liu 2.5 mg/kg tim

mng bng. Mt khc, kt qu tng quan h thng cho thy, amphetamin c th lm

tng nng DA trong no cao hn 10 ln so vi morphin. T c th thy tc

dng ca cc cht ma ty tng hp mnh hn ng k so vi ma ty c ngun gc

t nhin.

43

3.2. KIN NGH

Ma ty ngy cng c nhiu loi, c bit l s a dng ca ma ty tng hp.

Mi thuc nh hng n c th l khc nhau v mc gy nghin cng khng

ging nhau. im chung ca cc cht ma ty l u lm tng DA trong no. V vy

c th da vo thc o mc tng DA bng phng php thm tch micro so

snh mc hot lc tc dng ca cc cht ma ty, t xy dng bng tham chiu

nh gi mc mnh yu ca mi cht ma ty. Morphin v amphetamin l cht

in hnh trong cc loi ma ty v chng c coi nh l cc cht chun so

snh nh gi tc dng ca cc ma ty khc.

Trong nghin cu ny, chng ti tng quan h thng (systematic review) v s

thay i DA sau khi s dng cp tnh cc cht ma ty. V th chng ti hy vng

rng trong tng lai cn c thm nghin cu tng quan nh gi ton din nh

hng ca vic s dng mn tnh cc cht ma ty n cc t bo thn kinh

dopaminergic.

Mi lin h gia DA v cc cht ma ty c chng minh. C ch gy

nghin cng c th lin quan trc tip hoc gin tip n DA. T y chng ta c

th tin hnh cc nghin cu nh gi mc tnh trng nghin, mc tn

thng no do ma ty gy ra cng nh bin php cai nghin, gp phn lm sng t

thm trong cc nghin cu v dc l thn kinh phn t, c bit cc thuc lin

quan n ma ty.

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