Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in the Function of Brain Reward...

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?

Worried

Hopeless Grumpy

Listless

Mood in Rodents?

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

CREB (cAMP Response Element Binding Protein)

AMPA/GluR1Rs NMDARs

Gs Gi/o

G protein-coupled receptors

ATPcAMP

CaMKIV

alteredgeneexpression

L-type Ca2+channels

Neurotrophinreceptors

adenylate cyclase

CaMKII

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?

NAc VTA

Elevation of CREB with Engineered Viruses

NAc VTA

Blockade of CREB Function By Overexpressionof mCREB with Engineered Viruses

NAc VTA

pHSV PrpUC

cDNA (e.g. CREB, mCREB, LacZ)

HSV-1c Region

pBR 322

aHSV-1

packagingsite

SV-40 polyadenylation

Col E1ori

oris IE 4/5 Promoter

(Neve Lab)

Gene Transfer Using Viral Vectors

Increased Protein Expression Minimal Damage

Overview

1. CREB

Measurement of Drug Reward (and Aversion)

Effect of CREB Over Cocaine Doses

Dysphoria

Anhedonia

Carlezon et al., 1998

Intracranial Self-Stimulation (ICSS)in mCREB transgenic mice

ICSS Thresholds

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

120 WT

* *** **

Thresholds%

Forced Swim Test (FST)

SwimmingSwimming Immobile

Elevated CREB Increases Immobility in the FSTT

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

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

ATPcAMP

CaMKIV

alteredgeneexpression

L-type Ca2+channels

Neurotrophinreceptors

adenylate cyclase

CaMKII

TH BDNF

Dynorphin

Fos CRF

Overview

1. CREB

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

Stress Increases Dynorphin mRNAin the NAc

Stress = More DynorphinStress = More Dynorphin

Chartoff et al., unpublished

Sham FST FST + DMI

Biology & Behavior

DepressiveDepressiveBehaviorsBehaviors

Biology & Behavior

DepressiveDepressiveBehaviorsBehaviors

dynorphindynorphin

Clinical ImplicationsClinical Implications

Overview

1. CREB

U-69593 (kappa agonist) increases immobilityand decreases swimming

a U-69593 (mg/kg, IP) - FST b Locomotor Activity

10 mg/kg

3.0 mg/kg

1.0 mg/kg

0.3 mg/kg

0.1 mg/kg

acidic veh

immobility swimming climbing

*******

10 mg/kg

3.0 mg/kg

acidic veh

Mague et al., 2003

ANTI (IP) decreases immobilityand increases climbing

3.0 mg/kg

1.0 mg/kg

0.3 mg/kg

0.1 mg/kg

ANTI (mg/kg, IP) - FST

30003.0 mgkg

Locomotor Activity

Mague et al., 2003*ANTI: 5’-acetamidinoethylnaltrindole

Proposed Circuitry

Salvinorin A(kappa agonist)

Kappa-selective agonist

(Roth et al., 2002 )

Salvinorin A

Microdialysis (NAc)

% 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

** ** ** ****

Dopaminea

Serotonin

-40 -20 0 20 40 60 80 100 120

Time (min)% S e r o t o n i n

(Carlezon et al., 2005)

Abuse Liability of Kappa Antagonists?

Effect of kappa ligands on ICSSEffect of kappa ligands on ICSS

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

Locomotor ActivityLatency to Immobility

CBP/p300

RNAPol-II

““CREB-On”CREB-On”

““CREB-Off”CREB-Off”

Kappa-selective agonist

Salvia Divinorum

(Carlezon et al., JPET, in press)

Salvinorin A

Vehicle

********

******

Salvinorin A

Sal Veh 0.125 0.25 0.5 1.0 2.0 4.0

* ** **

Dose Salvinorin A (mg/kg, IP)

Salvinorin A

Microdialysis (NAc)

% 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

** ** ** ****

Dopaminea

Serotonin

-40 -20 0 20 40 60 80 100 120

Time (min)% S e r o t o n i n

Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in the Function of Brain Reward...

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