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The topography and functional
significance of the dopaminergic
dysfunction in schizophrenia
Anissa Abi-Dargham MD
Professor of Psychiatry
Vice Chair for Research, Department of Psychiatry
Stony Brook University
New York
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Abi-Dargham et al, Biol
Psychiatry cover, Jan
2017
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MOTOR COGNITIVE LIMBIC
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Presynaptic
Postsynaptic STR medium Spiny neuron
Tyrosine
hydroxylase
AADC
VMAT
DAT
COMTMAO
D2 receptor
Imaging the striatal dopaminergic synapse
D2 receptor
[18F]f-DOPA: synthesis and presynaptic storage (activity of AADC)
D2 receptor
Dopamine levels
(but also uptake in DA neurons, VMAT activity and uptake in vesicles, pH in vesicles, metabolism in cytoplasm…)
(but also affected by dopamine occupancy, internalization, affinity state…)
VMAT2 radiotracers: DTBZ
DAT radiotracer: BCIT, PE2I
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Dopamine “synthesis”Reith et al., 1994
Hietala et al., 1995, 1999
Lindstorm et al., 1999
Meyer-Lindenberg et al., 2002
McGowan et al., 2004
Nozaki S et al., 2009
Howes et al., 2009
D2 receptors
- Meta analyses -
Weinberger & Laruelle, 2001
Howes et al., 2012
D1 receptors Normal
DAT and VMAT2: Normal
Dopamine “release”- Amphetamine challenge -
Laruelle et al., 1996
Breier et al., 1997
Abi-Dargham et al., 1998
- AMPT -
Abi-Dargham et al., 2000
Kegeles et al., 2010
Presynaptic
Postsynaptic STR medium Spiny neuron
Tyrosine
hydroxylase
AADC
VMAT
DAT
COMTMAO
D2 receptor
STRIATAL dopamine alterations in schizophrenia
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Changes in Positive Symptoms After 6 Weeks of Antipsychotic Use (%)
AM
PT
-In
du
ced
In
cre
ase
in D
2A
vail
ab
ilit
y (
%)
r2=0.58
P=.001
High Synaptic Dopamine Predicts Treatment
Response at 6 Weeks
0
10
20
30
40
50
-60 -50 -40 -30 -20 -10 0
Abi-Dargham A et al. Proc Natl Acad Sci USA. Vol. 97:8104-8109.
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Demjaha et al, AJP, 2012
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Abi-Dargham et al, Biol
Psychiatry cover, Jan
2017
Kegeles et al,
Archives of Gen
Psychiatry, 2010
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AM
PT
-induced incre
ase in [
11C
]raclo
pride B
P
(% b
aselin
e)
VST preDCA preDPU postCA postPU
VST AST SMST
*
Healthy controls (n = 18) Patients with schizophrenia (n = 18)
* p < 0.05
Intrasynaptic dopamine in STR subdivisions in SCZ
, Kegeles et al, Archives of Gen Psychiatry, 2010
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Striatal Dopamine Release and Psychotic Symptoms[1
23I]IB
ZM
dis
pla
cem
ent (%
baselin
e)
Schizophrenia, n= 34 Dual Diagnosis, n=10
Change in Psychosis scores (PANSS)
rS = 0.69
(rP = 0.62)
ROSTRAL caudate
rP = 0.55
STRIATUM
Thompson et al, Mol Psychiatry 2012
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SCZ =20, HC = 21
∆B
PN
DC
on
str
ain
ed
2T
C
Regional Averages in displacement of radiotracer ± SD
DLPFC deficit in dopamine release capacity in SCZ
Slifstein et al, JAMA Psychiatry 2015
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SCZ =20, HC = 21
∆B
PN
DC
on
str
ain
ed
2T
C
Regional Averages in displacement of radiotracer ± SD
Generalized deficit in dopamine release capacity in SCZ
Slifstein et al, JAMA Psychiatry 2015
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Abi-Dargham et al, Biol
Psychiatry cover, Jan
2017
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Horga, Cassidy, Xu, Moore, Slifstein, Van Snellenberg and Abi-Dargham, JAMA Psychiatry 2016
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Switching off D2R OE
Or chronic haloperidol
Bi-directional Modulation Of Bridging Collaterals By Dopamine D2 Receptors
Genetic D2R
Up-regulation
Cazorla et al. 2012 J. Neuroscience
Cazorla et al. 2014 Neuron
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Where are we in the big scheme of things.....
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Weinstein et al, Biol Psychiatry, 2017
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Weinstein et al, Biol Psychiatry, 2017
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Weinstein et al, Biol Psychiatry, 2017
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Schultz et al., O’Doherty et al., Daw et al., Glimcher et al.
Prediction error
Reward/aversion/prediction/alerting
signal…
Go/ no Go balanced:
Go>>>>noGO
Connectivity
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• Does the dual phenotype (striatal excess , extrastriataldeficit) exsist at a single patient level (or just acrosspopulations with SCZ, some may have excess, othersdeficit?)
• If they co-occur within a single patient which is primary?
• What are the precise cellular mechanisms of dopamine dysregulation?
• Can local regulation of DA in the associative striatum bealtered? What are the factors at play?
• The link to symptoms:
• The functional properties of small and large circuits withinthe brain is affected by dopamine, and by dopaminergicdysregulation
• What are the precise mechanisms leading from abnormaldopamine kinetics to symptoms?
Where are we in the big scheme of things.....
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Weinstein et al, Biol Psychiatry, 2017
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Division of Translational Imaging
Mark Slifstein PhD
Roberto Gil, MD
Larry Kegeles, MD, PhD
Ragy Girgis, MD
Guillermo Horga, MDJared Van Snellenberg, PhD
Cliff Cassidy, PhD
Jodi Weinstein, MDXiaoyan Xu PhD
Yale collaborators:
Cyril D’ Souza, Robert Malison, Richard
Carson, Henry Huang, Nabeel Nabulsi
Funding: NIMH, NIDA, NARSAD
Conte Center
Eric Kandel, MD, PhD
Jonathan Javitch MD, PhD
Jeff Lieberman MD
Holly Moore, PhD
Steve Rayport, MD, PhD
Daphna Shohamy, PhD
Eleanor Simpson, PhD
Christoph Kellendonk, PhD
Rochester U:
Suzanne Haber, PhD
COLUMBIA UNIVERSITY
MEDICAL CENTER