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. Hcrt ko are narcoleptic 1 cm 1 cm 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 DRN Acc LDTg LC VTA BF PPTg NA Ach TMN 5-HT DA His (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. Hcrt-1 (5µg; n=9) Hcrt-1 + anti-Hcrt-1 (n=5) Saline (n=5) 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 (n=5) ShA (n=6) LgA 1h (n=5)

17. 160 120 80 40 0 1000 800 600 400 200 0 1 2 3 4 5 6 7 8 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. Cocaine SA Baseline (5 sessions) Extinction (13 sessions) Hcrt-1 challenge (1 session) 60 Active lever responses Inactive lever responses 50 40 Total responses / 2h Session 30 20 10 0 Average cocaine sessions Average last 3 extinction sessions Hcrt-1 (1.5 nmol) challenge Hcrt1 (icv) reinstates cocaine-seeking behavior

21. Blockade of both CRF and NE prevents Hcrt-induced reinstatement

22. 600 500 400 (n=5) (n=5) 300 Reinstatement in % of extinction 200 100 0 D-Phe (0.5 µg per side) + Hcrt-1 (0.25 µg per side) Hcrt-1 (0.25 µg per side) 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. Ben Boutrel Raphaëlle Winsky Chisa Suzuki Covadonga Pañeda George Koob Paul J. Kenny Athina Markou Acknowledgements TSRI Yale Tamas Horvath