Cocaine- and Extinction-InducedNeuroplasticity in AMPA Receptors Regulate

Drug-Seeking Behavior

DAVID W. SELF, PH.D.Associate Professor of Psychiatry and Neuroscience

The Seay Center for Basic and AppliedResearch in Psychiatric IllnessSouthwestern Medical Center

Drug-Induced Neuroplasticity in the Mesolimbic Dopamine System

DAVTA

Propensity forCocaine-Seeking

Behavior?

From PfC and amygdala

AMPARsLTP

Glu

White et al., 1995Zhang et al., 1997Ungless et al., 2001Saal et al., 2003

NAc

From PfC, hippocampus,amygdala, and thalamus

Glu

AMPARsLTD

White et al., 1995Thomas et al., 2001

Herpes Simplex (HSV) Viral Vectorfor In Vivo GluR1 Over-Expression

HSV-lacZHSV-GluR1 WT HSV-GluR1 S845AHSV-GluR1 S831AHSV-GluR1 Q582EHSV-GluR2 WT

Pore-deadQ582E

PKA-resistantS845A

PKC/CaMKII-resistantS831A

Adapted from Bredt and Nicoll, 2003

GluR1-derived sequences

Prokaryotic sequences

HSV-derived sequences

AmpR

Ori

Ori S

IE 4/5Promoter

InsertedTransgene

packaging/cleaving

SV-40Poly A

Reduced ExcitatoryInput to NAc

- Hypofrontality in humans(Volkow et al., 1992, 2000; London et al., 1999)

- Reduced basal extracellular glutamate

(Keys et al., 1998; Bell et al., 2000)

- Reduced AMPA response(White et al., 1995)

- LTD in PfC-NAc synapses w/sensitization

(Thomas et al., 2001)

NAc Glutamatergic Deficits in Cocaine Addiction

PfC

NAc VTADA

DA

DA

HippBehavioral

Disinhibition

Incentive Motivation

mRNA Levels

GluR1

GluR2

Ctrl WD EXTw/o

levers Ctrl

50% 61% 78%

56% 57% 64%Sutton et al., 2003

Cocaine-Seeking Behavior

0

20

40

60

80

100

Cue-InducedReinstatement

Dru

g-pa

ired

leve

r res

pons

es

0

20

40

60

80

100

ExtinctionLevel

GluR1 Protein Levels

-20

0

20

40

60

80

1 w

eek

WD

Parti

al E

XT

Grea

ter E

XTNoEXT

PartialEXT

FullEXT

***p < 0.001

% ∆

from

con

trol

p = 0.027

Sutton et al., 2003

-30

-10

10

30

50

70

90

HighRSTMT

LowRSTMT

***p = 0.03

% ∆

from

con

trol

HSV-GluR1/R2 reduces cocaine only

Cocaine

Extinction

Sham (14)

HSV-GluR1 (14)HSV-GluR2 (11)

HSV-LacZ (13)

*0

1

2

3

4

5

6

0

20

40

60

80

100

120

1 2 3 4 50

20

40

60

80

100

120

5 4 3 2 10

10

20

30

40

50

60

1 2 3 4

***

***

Extinction Day 1 ExtinctionLatencySelf-Administration

Coc

aine

inje

ctio

ns/4

hrs

Intra-NAcHSV Infusions

Test dayD

rug-

paire

d le

ver

HSV

-Glu

R1

HSV

-Glu

R2

Sham

HSV

-Lac

Z

Test

day

s

Hour

Sutton et al., 2003

Acknowledgements

VTA StudiesKwang-Ho ChoiScott Edwards

Collaborators

Southwestern Med. Ctr.Lisa MonteggiaAmelia Eisch

Harvard UniversityRachael Neve

Supported by NIDA grants DA 10460, DA 08227, DA 13796,and the Wesley Gilliland Professorship in Biomedical Research

NAc StudiesRyan BachtellKwang-Ho ChoiMike SuttonEric SchmidtKim Whisler