Title: Stress, Arousal and Addiction:
1Stress, Arousal and Addiction
- The hypocretin connection
Luis de Lecea, Ph.D. Department of Psychiatry and
Behavioral Sciences Stanford University
2Human narcolepsy-cataplexy
- Excessive daytime sleepiness
- Cataplexy
- Sleep paralysis
- Hypnagogic hallucinations
- Disturbed nocturnal sleep
Courtesy of Dr. Zuberi
Prevalence 1/2000, onset during
adolescence Treatment Psychostimulants (EDS) and
Antidepressants (Cataplexy)
3Narcolepsy is a disease of the hypocretinergic
system
mRNA in situ Hybridization
Hypocretin
MCH
Chemelli et al., 1999
Control
Narcoleptic
Peyron et al., 2000
4Two new members of the incretin neuropeptide
family
5Anatomy of the hypocretinergic system
(de Lecea et al., 1998 Peyron et al., 1998)
6The hypocretins in hyperarousal
7Hcrt and hyperarousal acute stress
Fabre et al.,
Fabre et al.
Reyes et al., 2003
8Hypocretins and stress response
?
9CRF terminals contact HCRT cell bodies
Winsky-Sommerer et al., (2004)
10CRF receptors are expressed in hcrt neurons
Winsky-Sommerer et al., (2004)
11CRF depolarizes HCRT neurons through CRFR1
Hcrt promoter
EGFP
Winsky- Sommerer et al., 2004
12Hcrt
Hcrt
13Does Hcrt affect brain reward?
14Hypocretin negatively regulates brain reward
140
130
120
110
Baseline ICSS Thresholds
100
90
80
Pre-drug
15 m
6 hr
12 hr
18 hr
24 hr
36 hr
48 hr
Time after injection
15Cocaine self-administration
Hcrt
16Hypocretin-1 does not affect cocaine intake
120
100
80
Percent of the baseline (saline infusion)
60
40
20
0
LgA 6h (n5)
ShA (n6)
LgA 1h (n5)
17Hcrt-1 does not change motivation for cocaine
intake
14
12
10
8
Number of infusion earned
Final ratio attained
Percent of the baseline
6
4
2
0
Saline infusion
Hcrt-1 5ug infusion
160
120
Percent of the baseline
80
Total number of responses
40
0
Saline
Hcrt-1 5ug
Day after
Sessions
18The addiction spiral
Acquisition
Positive effects on brain reward
Dependent state
Negative effects of withdrawal
Relapse
19Neuronal circuits involved in reinstatement
Shalev and Shaham, 2003
20Hcrt1 (icv) reinstates cocaine-seeking behavior
21Blockade of both CRF and NE prevents Hcrt-induced
reinstatement
22The BNST is involved in hypocretin-induced
reinstatement
23- 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?
24Hcrt receptor antagonist blocks stress-induced
reinstatement
25Addiction state
Footshock stress
Dopamine/ Ventral NE bundle
CRF
BNST
Hcrt
HPA axis
Alertness
Reinstatement of Drug seeking
26Acknowledgements
TSRI
Yale
- Ben Boutrel
- Raphaëlle Winsky
- Chisa Suzuki
- Covadonga Pañeda
- George Koob
- Paul J. Kenny
- Athina Markou
Tamas Horvath