cocaine: from animal models to pharmaceutical targets · pdf file1 day abstinence 21days- 3...
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cocaine: from animal models to pharmaceutical
targets
Antonello Bonci, M.D.
Gallo Center and Department of Neurology
UCSF, San Francisco, CA
No conflict of interest
A simple hypothesis:
Any addictive behavior depends on changes in electrical activity of specific brain regions
Genetic background
Environmental stimuli
A simple hypothesis:
Any addictive behavior depends on changes in electrical activity of specific brain regions
Genetic background
Environmental stimuli
Substance abuse
A simple hypothesis:
Any addictive behavior depends on changes in electrical activity of specific brain regions
Genetic background
Environmental stimuli
Why dopamine neurons?
Addiction
Apathy/motivation Depression
Aggressive behaviors
Sexual, appetitive behaviors Reward Deficiency Syndrome
Parkinson’s disease ADHD
Schizophrenia Dementias
Working memory
Behaviors produce by cocaine are modulated by dopamine neuron
activity
Behavioral sensitization
Cocaine self-administration
Relapse to cocaine seeking
My second wife
A fundamental cellular model of learning and memory:
long-term potentiation (LTP)
glutamate
What is LTP?
glutamate
dopamine
neuron
NMDAR
AMPAR
What is LTP?
glutamate
dopamine
neuron
NMDAR
AMPAR
CaMKII
Ca++
Are drugs of abuse capable of producing LTP?
Cocaine i.p. recording
24hrs
sensitization
48hrs
control
D-APV
cocaine
saline
A single injection of cocaine increases the AMPAR/NMDAR
ratio and produces LTP of AMPARs
0.0
0.2
0.4
0.6
0.8
1.0
1 day
AMPAR/NMDAR ratio
*
Ungless et al., Nature (2001)
0.0
0.2
0.4
0.6
0.8
1.0
1 day 5 days 10 days
Cocaine
Saline
The increase in the AMPAR/NMDAR ratio is long-lasting
*
*
AM
PA
R/N
MD
AR
ratio
Ungless et al., Nature (2001)
Behavioral sensitization requires NMDAR activation
LTP requires NMDAR activation
May be LTP underlies behavioral sensitization
Co-administration of cocaine + NMDAR antagonist blocks
increase of AMPAR/NMDAR ratio
and behavioral sensitization
0.0
0.2
0.4
0.6
0.8
1.0
Cocaine +
MK-801Saline +
MK-801
Ungless et al., Nature (2001)
4) What about cocaine self-administration?
Passive versus active choice of taking cocaine
Surgery
5 days recovery
Food deprivation
on last 2 days
2 overnight
food training
10 – 14 days cocaine self-
administration training
(0.25mg/kg/inf)
Sacrifice and
recording
19-28 days withdrawal
Sacrifice and
recording
Self-administration training and
whole-cell recording schedule
Chen et al., Neuron (2008)
Cocaine, but not food self-administration produces LTP in the VTA
during abstinence
1 day abstinence
Cocaine
Self-admin.
Food
Self-admin.
Yoked
cocaine0.0
0.2
0.4
0.6
0.8
1.0
1.2a
AM
PA
R/N
MD
AR
ratio
** **
Coc.Self-admin
FoodSelf-amin
YokedCocaine
b
0.0
0.2
0.4
0.6
0.8
1.0
1.2
AM
PA
R/N
MD
AR
ratio
Coc.Self-admin
FoodSelf-amin
YokedCocaine
21 days-3 months
of abstinence
*
50 pA
20 msec
Cocaine
Self-admin.
Food
Self-admin.
Yoked
cocaine
50 pA
20 msec
Chen et al., Neuron (2008)
****
**
Cocaine, but not food self-administration increases glutamate release
in the VTA during abstinence
mE
PS
C fre
qu
en
cy (
Hz) 7
6
5
4
3
2
1
0mE
PS
C fre
qu
en
cy (
Hz)7
6
5
4
3
2
1
0
1 day abstinence 21days- 3 months
abstinence
Coc.Self-admin
FoodSelf-amin
YokedCocaine
Coc.Self-admin
FoodSelf-amin
YokedCocaine
Chen et al., Neuron (2008)
Can we reduce cocaine self-administration and thus synaptic
plasticity?
Question:
Cue-induced relapse to cocaine is blocked by intra-VTA
injection of selective inhibitor of AMPAR-GluR2-lacking
subunits
0
10
20
30
40
50
60
70
80
90
100
Vehicle Naspm
Act
ive le
ver
pre
sses
Chen et al., in preparation
Cocaine-induced LTP in VTA is long-lasting but not
permanent
Chen et al., in preparation
Time course of natural reward versus cocaine
Behavioral Paradigm
30-90 s inter-trial interval 30-90 s inter-trial interval
10 s CS exposure
Sucrose pellet delivery
Rats are randomly assigned to CS+ or CS- group
and trained for 1 - 5 sessions.
•All rats receive 32 trials per behavioral session
•CS- rats receive the exact same exposure to stimuli
and sucrose pellets except pellet delivery is not
contingent upon CS presentation.
Cue-reward associations develop gradually
over multiple conditioning sessions
CS+ group CS- group
Stuber et al., Science (2008)
AMPA/NMDA ratio is transiently elevated during reward learning
50 ms
50 pANMDA
AMPA
50 ms
50 pANMDA
AMPA
50 ms
50 pA
NMDA
AMPA
50 ms
50 pA
NMDA
AMPA
50 ms
50 pA
NMDA
AMPA
50 ms
50 pA
NMDA
AMPA
Session 1 Session 5Session 3
CS+ group
CS- group
Stuber et al., Science (2008)
AMPA/NMDA ratio is transiently
elevated during reward learning
1 3 50.0
0.4
0.8
1.2CS+
CS-
Conditioning Session
synapse behavior
Stuber et al., Science (2008)
1 day 1 week3 days
LTP
time
The time course of LTP
2 weeks3 weeks
Single cocaine
1 day 1 week3 days
LTP
time
Repeated
Cocaine
2 weeks3 weeks
Single cocaine
The time course of LTP
1 day 1 week3 days
LTP
time
Cocaine self-administration
Repeated
Cocaine
2 weeks
?
3 weeks
Single cocaine
The time course of LTP
1 day 1 week3 days
LTP
time
Cocaine self-administration
Repeated
CocaineReward related learning
2 weeks
?
3 weeks
Single cocaine
The time course of LTP
1 day 1 week3 days
LTP
time
Cocaine self-administration
Repeated
CocaineReward related learning
The many faces of LTP in the VTA
2 weeks3 weeks
Single cocaineNaspm
How acute cocaine affects DA neuron activity
No cocaine
VTA neuron
How cocaine affects DA neuron activity
Acute cocaine
D2 -
VTA neuron
How cocaine affects DA neuron activity
D5 + NMDARs
VTA neuron
Acute cocaine
How cocaine affects DA neuron activity
D2 -D5 +GLU
VTA neuron
PFC
PPN
AMY
+
Acute cocaine
Tsai et al., Science (2009)
How cocaine affects DA neuron activity
AMPAGLU
VTA neuron
PFC
PPN
AMY
+
After chronic cocaine
+
How natural rewards affects DA neuron activity
AMPAGLU
VTA neuron
PFC
PPN
AMY
+
After training
+
How natural rewards affects DA neuron activity
AMPAGLU
VTA neuron
PFC
PPN
AMY
+
After training
+
?
Optogenetic Neuromodulation
• http://www.stanford.edu/group/dlab/optogenetics/index.html
• Application in rodent models
• Targeted expression in specific cell types
Genetic targeting of neuron subtypes using light-
sensitive proteins.
Feng Zhang, KD lab
ChR2 expressing neurons can provide an answer
Garret Stuber, Feng Zhang
PFC
VTA
EPSCs can be readily evoked by light
at accumbens and VTA synapses
AMPAR-mediated
EPSC (-70mV)
Blocked by 10 M CNQX
NMDAR-mediated
EPSC (+40mV)
Blocked by 50 M AP5
Garret Stuber, Emanuela Argilli, Wieke Van Leeuwen, Manouk Baches
Conclusions
-in vivo exposure to cocaine produces LTP in VTA DA neurons
- Voluntary versus passive drug exposure produces longer lasting LTP
-Longer time course of cocaine LTP versus natural rewards
-AMPAR antagonists as therapeutic agents against cocaine consumption
Conclusions
- Long-term potentiation (LTP) is a long-lasting increase in synaptic activity
- LTP represents a fundamental cellular phenomenon underlying normal
learning and memory processes
- A single cocaine exposure produces LTP, lasting about a week
-Natural rewards (food, sucrose) produce short-lasting LTP (1-3 days)
-Cocaine self-administration produces persistent LTP in dopamine neurons
(3 months)
Acknowledgements
Lab Members
Mark Ungless (ICL)
Woody Hopf
Garret Stuber
Emanuela Argilli
Billy Chen
Dennis Sparta
Kay Tye
Kimberly Kempadoo
Sarah Fischbach
Deborah Ahn
Michael Chiang
Shao-Jun Chang
Ling Wang
Saemi Chao
Steven Lieske
Gallo Center
Selena Bartlett
Howard Fields
Ulrike Heberlein
Patricia Janak
Bob Messing
Dorit Ron
Jennifer Whistler
Ray White
Linda Willbrecht
Viktor Kharazia
UCSF
Pam England
John Rubenstein
Lou Reichardt
Larry TecottThanks to NIDA, DoD and
State of California
Extramural
Karl Deisseroth
Luis deLecea
Rob Malenka
Richard Palmiter
Paul Phillips
Matthjis Verhage
Roy Wise
Collaborations