Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in
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Jacob P. Waletzky Memorial Lecture Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in Experience-Dependent Alterations in the Function of Brain Reward the Function of Brain Reward Systems: Systems: The Role of CREB The Role of CREB William A. Carlezon, Jr., Ph.D. Behavioral Genetics Laboratory Department of Psychiatry Harvard Medical School McLean Hospital
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Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in the Function of Brain Reward Systems: The Role of CREB. William A. Carlezon, Jr., Ph.D. Behavioral Genetics Laboratory Department of Psychiatry Harvard Medical School McLean Hospital. - PowerPoint PPT Presentation
Transcript of Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in
Jacob P. Waletzky Memorial LectureJacob P. Waletzky Memorial Lecture
Experience-Dependent Alterations inExperience-Dependent Alterations in the Function of Brain Reward Systems:the Function of Brain Reward Systems:
The Role of CREBThe Role of CREB
William A. Carlezon, Jr., Ph.D.Behavioral Genetics Laboratory
Department of PsychiatryHarvard Medical School
McLean Hospital
Addiction and Depressive DisordersAddiction and Depressive Disorders
• • High rates of co-morbidity in both men and womenHigh rates of co-morbidity in both men and women (Kessler et al., 1997).(Kessler et al., 1997).
• • Causal relationships can be difficult to establish.Causal relationships can be difficult to establish.
• • Addictive behaviors and depressive disorders haveAddictive behaviors and depressive disorders have common triggers (e.g., stress).common triggers (e.g., stress).
• • Studies of addiction may give us insights on depressive Studies of addiction may give us insights on depressive disorders, and vice-versa.disorders, and vice-versa.
Working Hypothesis
Addiction and Depressive DisordersInvolve Brain Reward Systems
Mood in Rodents?
Sad
Happy
Worried
Hopeless Grumpy
Listless
Mood in Rodents?
Sad
GrumpyHappy
Anhedonia
Reward Dysphoria
WorriedAnxiety
HopelessDespair
ListlessHypoactivity
Mood in RodentsMood in Rodents
• • rewardreward (feelings of pleasure) (feelings of pleasure)
• • anhedoniaanhedonia ( (reduced ability to experience rewarding ability to experience rewarding things as rewarding)things as rewarding)
• • dysphoriadysphoria (feelings of discomfort) (feelings of discomfort)
• • despairdespair (feelings of giving up) (feelings of giving up)
• • anxiety anxiety (feelings of apprehension, fear)(feelings of apprehension, fear)
• • hypoactivityhypoactivity (less active than normal) (less active than normal)
Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
CREB (cAMP Response Element Binding Protein)
AMPA/GluR1Rs NMDARs
Gs Gi/o
G protein-coupled receptors
Ca2+
PKA
ATPcAMP
CaM
MAPK
RSK
CaMKIV
CREB
CREB
P
P
alteredgeneexpression
CREB
L-type Ca2+channels
TrkB
Neurotrophinreceptors
adenylate cyclase
Gq
PLC
CaMKII
PDE
TH BDNF
Dynorphin
Fos CRF
Addictive Drugs Regulate CREB in the NAc
CREB phosphorylation
Turgeon et al., 1997
Drug Regulation of CREB
Are there behavioral correlates of CREBactivity in the NAc?
• Drug tolerance?
• Drug sensitization?
CREB
NAc VTA
Elevation of CREB with Engineered Viruses
Elevation of CREB with Engineered Viruses
CREB
NAc VTA
Blockade of CREB Function By Overexpressionof mCREB with Engineered Viruses
mCREB
NAc VTA
pHSV PrpUC
cDNA (e.g. CREB, mCREB, LacZ)
HSV-1c Region
pBR 322
aHSV-1
packagingsite
SV-40 polyadenylation
site
Amp
Col E1ori
oris IE 4/5 Promoter
(Neve Lab)
Gene Transfer Using Viral Vectors
Increased Protein Expression Minimal Damage
Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
Measurement of Drug Reward (and Aversion)
Effect of CREB Over Cocaine Doses
Ch
ang
e i
n T
ime
Sp
en
t in
Dru
g S
ide
(sec
)
Dysphoria
Anhedonia
Carlezon et al., 1998
Intracranial Self-Stimulation (ICSS)in mCREB transgenic mice
ICSS Thresholds
100%
Drugs of AbuseDrugs of Abuse(amphetamine, cocaine, opiates,
PCP, nicotine)
Aversive/ProdepressantsAversive/Prodepressants(drug withdrawal, lithium,
neuroleptics)
Intracranial Self-Stimulation (ICSS)in mCREB transgenic mice
.
Dose Cocaine (mg/kg, IP)
0.0 1.25 2.50.63 5.0 100
20
40
60
80
100
120 WT
* *** **
**
^^
mCREB
Thresholds%
Ba
se
line
Th
res
ho
lda
Forced Swim Test (FST)
SwimmingSwimming Immobile
Elevated CREB Increases Immobility in the FSTT
ime
(se
c)
Be
am
Bre
aks
(1
hr)
Latency to Immobility Locomotor Activity
HSV-mCREB
HSV-LacZ
HSV-CREB
Vehicle
CREB-On = More Depressive-like SignsCREB-On = More Depressive-like Signs
CREB-Off = Fewer Depressive-like SignsCREB-Off = Fewer Depressive-like Signs
Forced Swim Test (FST)
SwimmingSwimming Immobile
Forced Swimming Activates CREB in the NAc
Ind
uct
ion
(sw
im /
no
sw
im)
CREB in the NAc normally plays a role in reacting to stressCREB in the NAc normally plays a role in reacting to stress
Pliakas et al., 2001
Biology & Behavior
DrugsDrugsStressStress
CREBCREBIn NAcIn NAc
DepressiveDepressiveBehaviorBehavior
CREB Target GenesCREB Target Genes
CREB (cAMP Response Element Binding Protein)
AMPA/GluR1Rs NMDARs
Gs Gi/o
G protein-coupled receptors
Ca2+
PKA
ATPcAMP
CaM
MAPK
RSK
CaMKIV
CREB
CREB
P
P
alteredgeneexpression
CREB
L-type Ca2+channels
TrkB
Neurotrophinreceptors
adenylate cyclase
Gq
PLC
CaMKII
PDE
TH BDNF
Dynorphin
Fos CRF
Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
DynorphinDynorphin
• • It has CRE sites in its promoter (Douglass et al., 1994)It has CRE sites in its promoter (Douglass et al., 1994)
• • It is regulated by drugs of abuse (Hurd and Herkenham,It is regulated by drugs of abuse (Hurd and Herkenham, 1993; Daunais et al., 1993; Cole et al., 1995)1993; Daunais et al., 1993; Cole et al., 1995)
• • Kappa agonists are aversive rats (Bals-Kubik et al., 1993)Kappa agonists are aversive rats (Bals-Kubik et al., 1993)
• • Kappa agonists are aversive in people (Pfeiffer et al.,Kappa agonists are aversive in people (Pfeiffer et al., 1986)1986)
• • It is a kappa opioid receptor ligand (Chavkin et al., 1982)It is a kappa opioid receptor ligand (Chavkin et al., 1982)
CREB Increases Dynorphin mRNAin the NAc
CREB-On =CREB-On =More DynorphinMore Dynorphin
CREB-Off =CREB-Off =Less DynorphinLess Dynorphin
Carlezon et al., 1998
Stress Increases Dynorphin mRNAin the NAc
Stress = More DynorphinStress = More Dynorphin
Chartoff et al., unpublished
.
0
0.5
1
1.5
2
2.5
mR
NA
(d
yno
rph
in/
-act
in)
Sham FST FST + DMI
**
Biology & Behavior
DrugsDrugsStressStress
CREBCREBIn NAcIn NAc
DepressiveDepressiveBehaviorsBehaviors
Biology & Behavior
DrugsDrugsStressStress
CREBCREBIn NAcIn NAc
DepressiveDepressiveBehaviorsBehaviors
dynorphindynorphin
Clinical ImplicationsClinical Implications
Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
U-69593 (kappa agonist) increases immobilityand decreases swimming
.
a U-69593 (mg/kg, IP) - FST b Locomotor Activity
10
20
30
40
10 mg/kg
3.0 mg/kg
1.0 mg/kg
0.3 mg/kg
0.1 mg/kg
acidic veh
0
**
*
immobility swimming climbing
Me
an
Co
un
ts
Me
an
Co
un
ts
**
*******
10 mg/kg
3.0 mg/kg
acidic veh
0
500
1000
1500
2000
2500
3000
**
Mague et al., 2003
ANTI (IP) decreases immobilityand increases climbing
.
a
10
20
30
40
3.0 mg/kg
1.0 mg/kg
0.3 mg/kg
0.1 mg/kg
water
0
***
ANTI (mg/kg, IP) - FST
immobility swimming climbing
b
0
500
1000
1500
2000
2500
30003.0 mgkg
water
Locomotor Activity
Me
an
Co
un
ts
Me
an
Co
un
ts
** *
**
Mague et al., 2003*ANTI: 5’-acetamidinoethylnaltrindole
Proposed Circuitry
Carlezon et al., 2000
Proposed Circuitry
Carlezon et al., 2000
X X
Proposed Circuitry
Carlezon et al., 2000
X X
O
O
OO
O
O
O
O
Salvinorin A(kappa agonist)
Kappa-selective agonist
(Roth et al., 2002 )
O
O
O
O O
O
O
O
Salvinorin A
Microdialysis (NAc)
.
0
25
50
75
100
125
150
% D o p a m i n e
-40 -20 0 20 40 60 80 100 120
Time (min)
SalvA 1.0
SalvA 0.125
DMSO
** ** ** ****
*
Dopaminea
.
Serotonin
0
25
50
75
100
125
150
-40 -20 0 20 40 60 80 100 120
Time (min)% S e r o t o n i n
b
(Carlezon et al., 2005)
Abuse Liability of Kappa Antagonists?
Effect of kappa ligands on ICSSEffect of kappa ligands on ICSS
Effect of kappa ligands on ICSSEffect of kappa ligands on ICSS
Effect of kappa ligands on ICSSEffect of kappa ligands on ICSS
Effect of kappa ligands on ICSSEffect of kappa ligands on ICSS
O
O
OO
O
O
O
O
Salvinorin A(kappa agonist)
Medicinal Chemistry Program
Furan-ring derivatives
Lactone-ring derivativesC2 derivatives
C4 derivatives
Does CREB in the NAc Regulate Mood?
Carlezon & Konradi, 2004Carlezon & Konradi, 2004
AcknowledgementsAcknowledgementsCarlezon LabCarlezon LabAndrea Pliakas
Andreas ArvanitogiannisRebecca Ralph-Williams
Sonia GuedicheSteve MagueBrian Gilliss
Elena ChartoffHilarie Tomasiewicz
Mark TodtenkopfEdward Meloni
Alexandra JacksonJacqueline Marcus
Maria PapadopoulouJennifer DiNieriKatie FamousAndrew Smith
Jessica PohlmanAram ParsegianMelissa Stoos
Lyle GeretyTracie PaineDost Ongur
Allison KnollMatthew Barhight
Antonia Dow
Funding SourcesNIDA, NIMH, NARSAD
McLean LabsBruce Cohen, Christine KonradiRachael Neve, Susan Andersen
Special AcknowledgementsSpecial Acknowledgements
Waletzky FamilyWaletzky Family
Society for NeuroscienceSociety for Neuroscience
Kappa Antagonists have Antidepressant EffectsT
ime
(se
c)
Be
am
Bre
aks
(1
hr)
Locomotor ActivityLatency to Immobility
CBP/p300
.
P
CR
EB
P
CR
EB
HAT
CRE
mC
RE
B
P
CR
EB
X
CBP/p300
RNAPol-II
CRE
RNAPol-II
A
““CREB-On”CREB-On”
““CREB-Off”CREB-Off”
O
O
OO
O
O
O
O
Salvinorin A(kappa agonist)
Kappa-selective agonist
Salvia Divinorum
FST
(Carlezon et al., JPET, in press)
O
O
O
O O
O
O
O
Salvinorin A
.
0
10
20
30
40
2.0
1.0
0.5
0.25
0.125
Vehicle
Me
an
Co
un
ts
immobility swimming climbing
a b
Dis
tan
ce T
rave
led
(cm
)
0
500
1000
1500
2000
********
******
ICSS
O
O
O
O O
O
O
O
Salvinorin A
.
80
100
120
140
Sal Veh 0.125 0.25 0.5 1.0 2.0 4.0
* ** **
Dose Salvinorin A (mg/kg, IP)
Per
cent
Bas
elin
e T
hres
hold
0
(Carlezon et al., JPET, in press)
O
O
O
O O
O
O
O
Salvinorin A
Microdialysis (NAc)
.
0
25
50
75
100
125
150
% D o p a m i n e
-40 -20 0 20 40 60 80 100 120
Time (min)
SalvA 1.0
SalvA 0.125
DMSO
** ** ** ****
*
Dopaminea
.
Serotonin
0
25
50
75
100
125
150
-40 -20 0 20 40 60 80 100 120
Time (min)% S e r o t o n i n
b
(Carlezon et al., JPET, in press)
