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

Prevalence: 1/2000, onset during adolescenceTreatment: Psychostimulants (EDS) and

Antidepressants (Cataplexy)

Courtesy of Dr. Zuberi

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

Two new members of the incretin neuropeptide family

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

The hypocretins in hyperarousal

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

Hypocretins and stress response

?

CRF terminals contact HCRT cell bodies

Winsky-Sommerer et al., (2004)

CRF receptors are expressed in hcrt neurons

Winsky-Sommerer et al., (2004)

CRF depolarizes HCRT neurons through CRFR1

Winsky- Sommerer et al., 2004

Hcrt promoter EGFP

Hcrt

Hcrt

Does Hcrt affect brain reward?

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

Cocaine self-administration

Hcrt

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

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

The addiction spiral

Acquisition

Relapse

Negative effects of withdrawal

Dependent state

Positive effects on brain reward

Neuronal circuits involved in reinstatement

Shalev and Shaham, 2003

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

Blockade of both CRF and NE prevents Hcrt-induced reinstatement

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

***

• 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?

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

*

BNST

Footshock stress

Hcrt

CRF

HPA axis

Alertness

Addiction state

Dopamine/ Ventral NE bundle

Reinstatement of Drug seeking

Acknowledgements

• Ben Boutrel

• Raphaëlle Winsky

• Chisa Suzuki

• Covadonga Pañeda

• George Koob• Paul J. Kenny• Athina Markou

TSRIYale

Tamas Horvath