cocaine- and extinction-induced neuroplasticity in ampa receptors regulate
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Cocaine- and Extinction-Induced Neuroplasticity in AMPA Receptors Regulate Drug-Seeking Behavior . DAVID W. SELF, PH.D. Associate Professor of Psychiatry and Neuroscience The Seay Center for Basic and Applied Research in Psychiatric Illness Southwestern Medical Center. - PowerPoint PPT PresentationTRANSCRIPT
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