stress, arousal and addiction:
DESCRIPTION
Stress, Arousal and Addiction:. The hypocretin connection. Luis de Lecea, Ph.D. Department of Psychiatry and Behavioral Sciences Stanford University. Human narcolepsy-cataplexy. Excessive daytime sleepiness Cataplexy Sleep paralysis Hypnagogic hallucinations Disturbed nocturnal sleep. - PowerPoint PPT PresentationTRANSCRIPT
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Stress, Arousal and Addiction:The hypocretin connection
Luis de Lecea, Ph.D.
Department of Psychiatry and Behavioral Sciences
Stanford University
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Human narcolepsy-cataplexy
• Excessive daytime sleepiness
• Cataplexy• Sleep paralysis• Hypnagogic
hallucinations• Disturbed nocturnal sleep
Prevalence: 1/2000, onset during adolescenceTreatment: Psychostimulants (EDS) and
Antidepressants (Cataplexy)
Courtesy of Dr. Zuberi
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Control
1 cm
Narcoleptic
1 cm
Peyron et al., 2000
Narcolepsy is a disease of the hypocretinergic system
mRNA in situ Hybridization
Hyp
ocre
tinM
CH
Hcrt ko are narcoleptic
Chemelli et al., 1999
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Two new members of the incretin neuropeptide family
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Anatomy of the hypocretinergic systemAnatomy of the hypocretinergic system
(de Lecea et al., 1998; Peyron et al., 1998)(de Lecea et al., 1998; Peyron et al., 1998)
LCLC
NA
LDTgLDTg
PPTgPPTgBFBF
Ach
VTAVTA
AccAcc
DA
TMNTMN
His
DRNDRN
5-HT
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The hypocretins in hyperarousal
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Hcrt and hyperarousal: acute stress
0
1000
2000
3000
4000
5000
6000
7000
8000
Hypothalamus Dorsal Raphe LocusCoeruleus
Hc
rt
1 (
pg
/mg
pro
tein
)
control
restraint stress
Fabre et al.
**
Fabre et al.,
Reyes et al., 2003
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Hypocretins and stress response
?
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CRF terminals contact HCRT cell bodies
Winsky-Sommerer et al., (2004)
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CRF receptors are expressed in hcrt neurons
Winsky-Sommerer et al., (2004)
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CRF depolarizes HCRT neurons through CRFR1
Winsky- Sommerer et al., 2004
Hcrt promoter EGFP
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Hcrt
Hcrt
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Does Hcrt affect brain reward?
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8080
9090
100100
110110
120120
130130
140140Hcrt-1 (5µg; n=9)Hcrt-1 (5µg; n=9)
Saline (n=5)Saline (n=5)
Hcrt-1 + anti-Hcrt-1 Hcrt-1 + anti-Hcrt-1 (n=5)(n=5)
Pre-drugPre-drug 15 m15 m 6 hr6 hr 12 hr12 hr 18 hr18 hr 24 hr24 hr 36 hr36 hr 48 hr48 hr
Time after injectionTime after injection
% B
ase
line IC
SS T
hre
shold
s%
Base
line IC
SS T
hre
shold
s
********
####
Hypocretin negatively regulates brain reward
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Cocaine self-administration
Hcrt
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00
2020
4040
6060
8080
100100
120120
ShA (n=6)ShA (n=6) LgA 1h (n=5)LgA 1h (n=5) LgA 6h (n=5)LgA 6h (n=5)
Perc
ent
of
the b
ase
line (
salin
e infu
sion)
Perc
ent
of
the b
ase
line (
salin
e infu
sion)
Hypocretin-1 does not affect Hypocretin-1 does not affect cocaine intakecocaine intake
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00
200200
400400
600600
800800
10001000
11 22 33 44 55 66 77 88
00
22
44
66
88
1010
1212
1414
Num
ber
of
infu
sion e
arn
ed
Num
ber
of
infu
sion e
arn
ed
Tota
l num
ber
of
resp
onse
sTota
l num
ber
of
resp
onse
s
Salin
e infu
sion
Salin
e infu
sion
Hcr
t-1
5ug infu
sion
Hcr
t-1
5ug infu
sion Final ra
tio a
ttain
ed
Final ra
tio a
ttain
ed
SessionsSessions
00
4040
8080
120120
160160
00
4040
8080
120120
160160
Perc
en
t of
the b
ase
line
Perc
en
t of
the b
ase
line
Perc
en
t of
the b
ase
line
Perc
en
t of
the b
ase
line
SalineSaline Hcrt-1 5ugHcrt-1 5ug Day afterDay after
Hcrt-1 does not change motivation for cocaine intake
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The addiction spiral
Acquisition
Relapse
Negative effects of withdrawal
Dependent state
Positive effects on brain reward
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Neuronal circuits involved in reinstatement
Shalev and Shaham, 2003
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00
1010
2020
3030
4040
5050
6060
Average cocaineAverage cocainesessionssessions
Tota
l re
sponse
s /
2h
Sess
ion
Tota
l re
sponse
s /
2h
Sess
ion
Average last 3 extinctionAverage last 3 extinctionsessionssessions
Hcrt-1 (1.5 nmol) challengeHcrt-1 (1.5 nmol) challenge
Active lever responses Inactive lever responses
Cocaine SA Baseline (5 sessions)Cocaine SA Baseline (5 sessions) Hcrt-1 challenge (1 session)Hcrt-1 challenge (1 session)Extinction (13 sessions)Extinction (13 sessions)
Hcrt1 (icv) reinstates cocaine-Hcrt1 (icv) reinstates cocaine-seeking behaviorseeking behavior
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Blockade of both CRF and NE prevents Hcrt-induced reinstatement
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0
100
200
300
400
500
600
Hcrt-1 (0.25 µg per side)D-Phe (0.5 µg per side)
+ Hcrt-1 (0.25 µg per side)
Rei
nsta
tem
ent
in %
of
ext
inct
ion
(n=5)(n=5)
The BNST is involved in hypocretin-induced reinstatement
***
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• Stress induces CRF• CRF stimulates hcrt neurons
• CRF produces reinstatement• Hcrt produces reinstatement
• CRF-R antagonists block stress-induced reinstatement
• Do Hcrt antagonists block stress-induced reinstatement?
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0
20
40
60
80
100
120
Baseline Vehicle + Footshock Baseline SB334867 + Footshock
# le
ver
pre
sses
/ se
ssio
n
Hcrt receptor antagonist blocks stress-induced reinstatement
*
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BNST
Footshock stress
Hcrt
CRF
HPA axis
Alertness
Addiction state
Dopamine/ Ventral NE bundle
Reinstatement of Drug seeking
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Acknowledgements
• Ben Boutrel
• Raphaëlle Winsky
• Chisa Suzuki
• Covadonga Pañeda
• George Koob• Paul J. Kenny• Athina Markou
TSRIYale
Tamas Horvath