Stress, Arousal and Addiction:

1
Stress, Arousal and Addiction

• The hypocretin connection

Luis de Lecea, Ph.D. Department of Psychiatry and
Behavioral Sciences Stanford University
2
Human 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)
3
Narcolepsy is a disease of the hypocretinergic
system
mRNA in situ Hybridization
Hypocretin
MCH
Chemelli et al., 1999
Control
Narcoleptic
Peyron et al., 2000

4
Two new members of the incretin neuropeptide
family
5
Anatomy of the hypocretinergic system
(de Lecea et al., 1998 Peyron et al., 1998)
6
The hypocretins in hyperarousal
7
Hcrt and hyperarousal acute stress

Fabre et al.,
Fabre et al.
Reyes et al., 2003
8
Hypocretins and stress response
?
9
CRF terminals contact HCRT cell bodies
Winsky-Sommerer et al., (2004)
10
CRF receptors are expressed in hcrt neurons
Winsky-Sommerer et al., (2004)
11
CRF depolarizes HCRT neurons through CRFR1
Hcrt promoter
EGFP
Winsky- Sommerer et al., 2004
12
Hcrt
Hcrt
13
Does Hcrt affect brain reward?
14
Hypocretin 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
15
Cocaine self-administration
Hcrt
16
Hypocretin-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)
17
Hcrt-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
18
The addiction spiral
Acquisition
Positive effects on brain reward
Dependent state
Negative effects of withdrawal
Relapse
19
Neuronal circuits involved in reinstatement
Shalev and Shaham, 2003
20
Hcrt1 (icv) reinstates cocaine-seeking behavior
21
Blockade of both CRF and NE prevents Hcrt-induced
reinstatement
22
The 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?

24
Hcrt receptor antagonist blocks stress-induced
reinstatement

25
Addiction state
Footshock stress
Dopamine/ Ventral NE bundle
CRF
BNST
Hcrt
HPA axis
Alertness
Reinstatement of Drug seeking
26
Acknowledgements
TSRI
Yale

• Ben Boutrel
• Raphaëlle Winsky
• Chisa Suzuki
• Covadonga Pañeda
• George Koob
• Paul J. Kenny
• Athina Markou

Tamas Horvath