cocaine: from animal models to pharmaceutical targets · pdf file1 day abstinence 21days- 3...

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