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

Abi-Dargham et al, Biol

Psychiatry cover, Jan

2017

MOTOR COGNITIVE LIMBIC

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

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

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.

Demjaha et al, AJP, 2012

Abi-Dargham et al, Biol

Psychiatry cover, Jan

2017

Kegeles et al,

Archives of Gen

Psychiatry, 2010

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

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

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

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

Abi-Dargham et al, Biol

Psychiatry cover, Jan

2017

Horga, Cassidy, Xu, Moore, Slifstein, Van Snellenberg and Abi-Dargham, JAMA Psychiatry 2016

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

Where are we in the big scheme of things.....

Weinstein et al, Biol Psychiatry, 2017

Weinstein et al, Biol Psychiatry, 2017

Weinstein et al, Biol Psychiatry, 2017

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

• 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.....

Weinstein et al, Biol Psychiatry, 2017

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