Jacob P. Waletzky Memorial Lecture

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Jacob P. Waletzky Memorial Lecture Experience-Dep
endent 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
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Addiction and Depressive Disorders
High rates of co-morbidity in both men and
women (Kessler et al., 1997).
Causal relationships can be difficult to
establish.
Addictive behaviors and depressive disorders
have common triggers (e.g., stress).
Studies of addiction may give us insights on
depressive disorders, and vice-versa.
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Working Hypothesis
Addiction and Depressive Disorders Involve Brain
Reward Systems
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Mood in Rodents?
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Mood in Rodents?
Grumpy
Happy
Hopeless
Reward
Dysphoria
Despair
Sad
Worried
Listless
Anhedonia
Anxiety
Hypoactivity
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Mood in Rodents
reward (feelings of pleasure) anhedonia
(reduced ability to experience rewarding
things as rewarding) dysphoria (feelings of
discomfort) despair (feelings of giving
up) anxiety (feelings of apprehension,
fear) hypoactivity (less active than normal)
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Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
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Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
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CREB (cAMP Response Element Binding Protein)
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Addictive Drugs Regulate CREB in the NAc
CREB phosphorylation
Turgeon et al., 1997
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Drug Regulation of CREB
Are there behavioral correlates of CREB activity
in the NAc? Drug tolerance? Drug
sensitization?
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Elevation of CREB with Engineered Viruses
CREB
VTA
NAc
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Elevation of CREB with Engineered Viruses
CREB
VTA
NAc
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Blockade of CREB Function By Overexpression of
mCREB with Engineered Viruses
mCREB
VTA
NAc
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a HSV-1 packaging site
pBR 322
Amp
SV-40 polyadenylation site
Col E1 ori
pHSV PrpUC
oris
IE 4/5 Promoter
HSV-1 c Region
cDNA (e.g. CREB, mCREB, LacZ)
(Neve Lab)
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Gene Transfer Using Viral Vectors
Increased Protein Expression Minimal
Damage
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Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
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Measurement of Drug Reward (and Aversion)
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Effect of CREB Over Cocaine Doses
Change in Time Spent in Drug Side (sec)

Carlezon et al., 1998
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Intracranial Self-Stimulation (ICSS) in mCREB
transgenic mice
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ICSS Thresholds
100
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Intracranial Self-Stimulation (ICSS) in mCREB
transgenic mice
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Forced Swim Test (FST)
Swimming
Immobile
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Elevated CREB Increases Immobility in the FST
Latency to Immobility
Locomotor Activity
Time (sec)
Beam Breaks (1 hr)
CREB-On More Depressive-like Signs
CREB-Off Fewer Depressive-like Signs
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Forced Swim Test (FST)
Swimming
Immobile
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Forced Swimming Activates CREB in the NAc
Induction (swim / no swim)

CREB in the NAc normally plays a role in reacting
to stress
Pliakas et al., 2001
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Biology Behavior
CREB In NAc
Drugs Stress
Depressive Behavior
CREB Target Genes
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CREB (cAMP Response Element Binding Protein)
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Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
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Dynorphin
It is a kappa opioid receptor ligand (Chavkin
et al., 1982)
It has CRE sites in its promoter (Douglass et
al., 1994)
It is regulated by drugs of abuse (Hurd and
Herkenham, 1993 Daunais et al., 1993 Cole et
al., 1995)
Kappa agonists are aversive in people
(Pfeiffer et al., 1986)
Kappa agonists are aversive rats (Bals-Kubik
et al., 1993)
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CREB Increases Dynorphin mRNA in the NAc
CREB-On More Dynorphin

CREB-Off Less Dynorphin
Carlezon et al., 1998
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Stress Increases Dynorphin mRNA in the NAc

Stress More Dynorphin
Chartoff et al., unpublished
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Biology Behavior
Drugs Stress
CREB In NAc
Depressive Behaviors
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Biology Behavior
Drugs Stress
CREB In NAc
Depressive Behaviors
dynorphin
Clinical Implications
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Overview
1. CREB
2. Functional role of CREB in the NAc
3. CREB and dynorphin
4. Kappa antagonists and agonists
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U-69593 (kappa agonist) increases immobility and
decreases swimming
Mague et al., 2003
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ANTI (IP) decreases immobility and increases
climbing
ANTI 5-acetamidinoethylnaltrindole
Mague et al., 2003
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Proposed Circuitry
Carlezon et al., 2000
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Proposed Circuitry
X
X
Carlezon et al., 2000
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Proposed Circuitry
X
X
Carlezon et al., 2000
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Kappa-selective agonist
O
O
O
O
O
O
O
O
Salvinorin A
(kappa agonist)
(Roth et al., 2002 )
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Salvinorin A
Microdialysis (NAc)
(Carlezon et al., 2005)
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Abuse Liability of Kappa Antagonists?
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Effect of kappa ligands on ICSS
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Effect of kappa ligands on ICSS
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Effect of kappa ligands on ICSS
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Effect of kappa ligands on ICSS
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Medicinal Chemistry Program
O
Furan-ring derivatives
O
C2 derivatives
O
Lactone-ring derivatives
O
O
O
O
O
C4 derivatives
Salvinorin A
(kappa agonist)
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Does CREB in the NAc Regulate Mood?
Carlezon Konradi, 2004
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Acknowledgements
Carlezon Lab
Andrea Pliakas Andreas Arvanitogiannis Rebecca
Ralph-Williams Sonia Guediche Steve Mague Brian
Gilliss Elena Chartoff Hilarie Tomasiewicz Mark
Todtenkopf Edward Meloni Alexandra
Jackson Jacqueline Marcus Maria
Papadopoulou Jennifer DiNieri Katie Famous Andrew
Smith Jessica Pohlman Aram Parsegian Melissa
Stoos Lyle Gerety Tracie Paine Dost Ongur Allison
Knoll Matthew Barhight Antonia Dow
Funding Sources NIDA, NIMH, NARSAD
McLean Labs Bruce Cohen, Christine
Konradi Rachael Neve, Susan Andersen
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Special Acknowledgements
Waletzky Family
Society for Neuroscience
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Kappa Antagonists have Antidepressant Effects
Locomotor Activity
Latency to Immobility
Time (sec)
Beam Breaks (1 hr)
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CRE
CREB-On
CREB-Off
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Kappa-selective agonist
Salvinorin A
(kappa agonist)
Salvia Divinorum
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Salvinorin A
FST
(Carlezon et al., JPET, in press)
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Salvinorin A
ICSS
(Carlezon et al., JPET, in press)
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Salvinorin A
Microdialysis (NAc)
(Carlezon et al., JPET, in press)