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 Function of Brain Reward Systems: The.
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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
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)