SENSORY AFFERENTS
description
Transcript of SENSORY AFFERENTS
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SENSORY AFFERENTS MOTOR OUTPUTS
Psyche
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Prefrontal Cortex
Sept/Acc
Amygdala
Hippocampus
HT
VTA/SN
DADA
DADA
DADADADA
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PLEASUREPLEASURE
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THE WORD « ADDICTION »THE WORD « ADDICTION »
OLD FRENCHOLD FRENCH : « ETRE ADDICTE »
TO PAY ONE’S DEBTS
ENGLISHENGLISH : TO BE ADDICTED TO DRUGS
ADDICTION
DEBTS ?
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OLD FRENCHOLD FRENCH : ETRE ADDICTE
TO PAY ONE’S DEBTS
ENGLISH ENGLISH : TO BE ADDICTED TO DRUGS
ADDICTION
DEBTS
?
THE WORD « ADDICTION »THE WORD « ADDICTION »
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OLD FRENCHOLD FRENCH : ETRE ADDICTE
TO PAY ONE’S DEBTS
ENGLISHENGLISH : TO BE ADDICTED TO DRUGS
ADDICTION
DEBTS
PLEASUREPLEASURE
THE WORD « ADDICTION »THE WORD « ADDICTION »
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synapticsynapticcleftcleft
Post-synapticPost-synapticneuronneuronDopamine receptorsDopamine receptors
DopamineDopamine
CocaineCocaine
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INJECTION PUMP
COMPUTER
ACTIVE HOLE
INACTIVE HOLE
SELF-ADMINISTRATION
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Rocha et al., 1998
COCAINE
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0000
200200
400400
600600
800800
10001000
12001200
1 2 3 4 5 6 7 8 9
3030252520201515101055
Time (days)
Loc
om
oto
r a
ctiv
ity (
cou
nts
/60
min
)L
oco
mo
tor
act
ivity
(co
un
ts/6
0 m
in)
14001400
16001600
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0
500
1000
1500
2000
2500
Am
phét
amin
e
NA
(%
basa
l)
0
50
100
150
Am
phét
amin
e
Acti
vit
é l
ocom
otr
ice
(¼ t
our
par
5 m
in)
-80 -40 0 40 80 120 160 200
Time (min)
acuteRepeat.(withdraw. 4-days)
Frontal Cortex
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acute
repeat.
repeat. (withdraw. 1-month)
(withdraw. 4-days)
Am
ph
.
2500
2000
1500
1000
500
NE
(%
bas
elin
e)
A
0
100
50
150
0
Lo
com
oto
r ac
tivi
ty
(1/4
tu
rn p
er 5
min
.)
B
Time (min.)0-40 40 80 120 160 200
Frontal cortex
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D1
D2
AMPAGABAA
Glu
PCF
VTA
NAcc GABA
GABA
DAGABA
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5-HT2A
α1b
D2
D1
LC
Glu
PCF
VTA
NAcc
GABA
NA
GABA
5-HTGABA
-GABA
DAGABA
GABA
AMPAGABAA
DR
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α1b-R
D1
5-HT2A
α1b
D2
LC
Glu
PCF
VTA
NAcc
GABA
NA
GABA
5-HTGABA
GABA
DAGABA
GABA
AMPAGABAA
DR
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α1b-R
5-HT2A
α1b
D2
D1
LC
Glu
PFC
VTA
NAcc
GABA
NA
GABA
5-HTGABA
GABA
DAGABA
GABA
AMPAGABAA
DRD 5-HT2AR
NA/ 5-HT COUPLING UNCOUPLINGNA/ 5-HT COUPLING UNCOUPLING
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5-HT2ARα1bRD2RD1R
LC
Glu
CPF
ATV
GABA
NA5-HTGABA
DA
GABA
RD
α1b-R
5-HT2AR
Glutamate R
NA/ 5-HT HYPERREACTIVITY AND DESYNCHRONIZATIONNA/ 5-HT HYPERREACTIVITY AND DESYNCHRONIZATION
UNCOUPLING INDUCESUNCOUPLING INDUCES
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REPEATED DRUGS OF ABUSE
UNCOUPLING NA/5-HT
NA/5-HT HYPERREACTIVITY AND DESYNCHRONIZATION
CHRONIC DISTRESS
BECAUSE DRUGS OF ABUSE ARTIFICIALLY RE-COUPLE BECAUSE DRUGS OF ABUSE ARTIFICIALLY RE-COUPLE
AND BRING TEMPORARY RELIEFAND BRING TEMPORARY RELIEF
WHY DO ADDICTS TAKE DRUGS ?
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No predictionReward occurs
Reward predictedReward occurs
Reward predictedNo reward occurs
(No CS)(No CS) RR
CSCS RR
CSCS (No R)(No R)-1-1 00 11 2s2s
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ABSENCE D’EFFET HYPERLOCOMOTEUR DE LA NICOTINE CHEZ LA SOURIS
Saline
200 250 3000
100
200
Ac
tivi
té lo
com
otr
ice
(1/
4 to
ur
pa
r 1
0 m
in.)
D-amphetamine (2 mg/kg)
200 250 3000
100
200
Morphine (7.5 mg/kg)
200 250 3000
100
200
Nicotine (1 mg/kg)
200 250 3000
100
200
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EFFET HYPERLOCOMOTEUR DE LA NICOTINE CHEZ LA SOURIS PRE-TRAITEE PAR LA TRANYLCYPROMINE
Activité locomotrice (1/4 tour par 10 min.)
Temps (min.)
0 50 100 150 200 250 3000
250
500
Tranyl (10 mg/kg) - nicotine (1 mg/kg)Tranyl - saline
Saline - nicotineSaline - saline
*******
***
******
*
Tra
nyl
/ S
alin
e
Nic
otin
e /
Sa
line
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AUTO-ADMINISTRATION
(RENFORCE)(NON RENFORCE)
RNR
Cocaine (500 Ug/k, iv)
1 2 3 4 50
25
50
75
100
Temps (jours)
Saline (iv)
1 2 3 4 50
25
50
75
100
R
NR
Temps (jours)
Ré
po
nse
s (/
3h
)
Nicotine (30 Ug/kg, iv)
1 2 3 4 50
25
50
75
100
Temps (jours)
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AUTO-ADMINISTRATION DE NICOTINECHEZ LE RAT PRE-TRAITE PAR LA TRANYLCYPROMINE
Tranyl (ip) Saline (iv)
1 2 3 4 50
25
50
75
100
RNR
Tranyl (ip) Nicotine (30 ug/kg, iv)
1 2 3 4 50
25
50
75
100
Temps (jours)
Rép
onse
s (/
3heu
res)
***
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salineTranylNicoacute
saline
acuteTranyl/NicoTranyl/Nico + SR/Pz
NE
(%
of
bas
elin
e)
A B
5-H
T (
% o
f b
ase
lin
e)
Time (min) Time (min)
C D
d-amphetamine
para-chloro-amphetamine
0 40 80 120-40 160 200 0 40 80 120-40 160 200
0
500
1000
0
500
1000
1500
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salineTranylNicoacute
saline
acuteTranyl/NicoTranyl/Nico + SR/Pz
NE
(%
of
bas
elin
e)
A B
5-H
T (
% o
f b
ase
lin
e)
Time (min) Time (min)
C D
d-amphetamine
para-chloro-amphetamine
0 40 80 120-40 160 200 0 40 80 120-40 160 200
0
500
1000
0
500
1000
1500
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0
500
1000
1500
PC
A
5-H
T (
% b
asel
ine)
-40 0 40 80 120 160 2000
50
100
150
Time (min)
Lo
com
oto
r ac
tivity
(¼ tu
rn p
er 5
min
)
-40 0 40 80 120 160 2000
50
100
150
Time (min)
Lo
com
oto
r ac
tivity
(¼ tu
rn p
er 5
min
)
0
250
500
750
1000
1250
Am
ph
.
NE
(%
bas
elin
e)
Repeated saline- - - - -
Repeated (tranyl/nico)_ _ Repeated (tranyl/nico + SCH)Repeated (SR/Pz)Repeated (tranyl/nico + SR/Pz)
Repeated (SCH)
C
D
A
B
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-10 0 10 20 30 40 500
10
20
30
40
50
WA
Y
nic
o
pretreat. (WAY + nico)
pretreat. (saline + nico)pretreat. (WAY + saline)
Time (min)
Lo
com
oto
r ac
tiv
ity
(¼ t
urn
/ m
in)
B
-10 0 10 20 30 40 500
10
20
30
40
50sa
line
/ WA
Y
sa
lin
e /
nic
o
saline + nicoWAY + salineWAY + nico
Time (min)
Lo
com
oto
r ac
tiv
ity
(¼ t
urn
/ m
in)
A
0
10
20
30 pretreat. (WAY + saline)
pretreat. (saline + nico)
pretreat. (WAY + nico)
sal nico WAY WAY + nico
a a a
b
Lo
com
oto
r ac
tiv
ity
(¼ t
urn
/ 1
0 m
in)
C
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0
500
1000
1500
PC
A
5-H
T (
% b
asel
ine)
-40 0 40 80 120 160 2000
50
100
150
Time (min)
Lo
com
oto
r ac
tivity
(¼ tu
rn p
er 5
min
)
-40 0 40 80 120 160 2000
50
100
150
Time (min)
Lo
com
oto
r ac
tivity
(¼ tu
rn p
er 5
min
)
0
250
500
750
1000
1250
Am
ph
.
NE
(%
bas
elin
e)
C
D
A
B
Repeated saline Repeated (WAY + saline) Repeated (WAY + Nico)
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PROPOSITIONS ET OBSERVATIONSPROPOSITIONS ET OBSERVATIONS
- L’addiction résulte d’un découplage des neurones NA et 5-HT.
- Ce découplage (obtenu avec l’amphétamine. la cocaïne, la morphine et l’alcool) est dû à la stimulation intense et répétée des récepteurs 1b-adrénergiques et/ou 5-HT2A.
- Le découplage n’est pas obtenu avec la nicotine seule.
- Le découplage est obtenu en présence de nicotine + IMAO ou de nicotine + un antagoniste des récepteurs 5-HT1A.
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CONCLUSIONSCONCLUSIONSCONCLUSIONSCONCLUSIONS
La nicotine n’est pas addictive par elle-même.
Elle le devient mélangée au tabac car les IMAOs qu’il contient
désensibilisent les récepteurs 5-HT1A.
Anne-Sophie Villégier (SFT)/ Lucas Salomon (MRT)/Christophe Lanteri (MILDT)
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REMERCIEMENTSREMERCIEMENTSREMERCIEMENTSREMERCIEMENTS
Fabrice TroveroFabrice Trovero
Agnès AuclairAgnès Auclair
Gérard BlancGérard Blanc
Gérard GodeheuGérard Godeheu
Vanessa HouadesVanessa Houades
Yvette TorrensYvette Torrens
Laurent DarracqLaurent Darracq
Emilie DoucetEmilie Doucet
Anne-Sophie VillégierAnne-Sophie Villégier
Christophe LanteriChristophe Lanteri
Lucas SalomonLucas Salomon
Candice DrouinCandice Drouin
Jacques GlowinskiJacques GlowinskiJay Gingrich
Michel Hamon
Laurence Lanfumey
Joëlle Adrien
Sandra Jimena Hernández Vallejo
Susanna Cotecchia
CollaborationsCollaborations
Sylvie Granon
Jean-Pierre Changeux
Philip Seeman
Patricia CougnotPatricia Cougnot
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acute
repeat.
repeat. (withdraw. 1-month)
(withdraw. 4-days)
Am
ph
.
2500
2000
1500
1000
500
NE
(%
bas
elin
e)
A
0
100
50
150
0
Lo
com
oto
r ac
tivi
ty
(1/4
tu
rn p
er 5
min
.)
B
Time (min.)0-40 40 80 120 160 200
Frontal cortex
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-60 -40 -20 0 20 40 60 80 100 1200
50
100
150
200
250
-60 -40 -20 0 20 40 60 80 100 1200
50
100
150
200
250
LO
CO
MO
TO
RA
CT
IVIT
Y(1
/4 tu
rn p
er
5-m
in)
-100 -60 -20 20 60 100 140
50
100
150
200
DO
PA
MIN
E(%
/ W
T b
asa
l)
-100 -60 -20 20 60 100 140
50
100
150
200
Saline – Morphine (20 mg/kg)
SR46349B - Morphine
Injection AIGUË Morphine / test SR46349B
α1b- AR KOWT