Transcript Slide 1

Endogenous Opioid Regulation of Goal-Directed
and Habitual Behavior
Kate M. Wassum, Ingrid C. Cely, Dr. Sean B. Ostlund,
Nigel T. Maidment, Dr. Bernard W. Balleine
Charles Drew University of Medicine and Science
4th Annual Drug Abuse Research Symposium
September 26th 2008
Dr.
How and Where are Opioid Receptors Involved in
Goal-Directed Behavior?
Opioid
Receptors
PFC
MDT
Incentive
Value
CeN
DMS
DLS
BLA
NAc NAs
VP
VTA
How are opioid receptors in the basolateral amygdala,
ventral pallidum and nucleus accumbens shell involved in
affective and incentive value aspects of reward-related
behavior?
Parsing Reward during Goal-Directed Instrumental
Behavior
• Reward Palatability
Affective component of reward consumption. ‘Liking’
Reflected in taste reactivity or licking frequency.
• Incentive Value
Extinction Response
Rate
The relative significance of a specific reward outcome that is used to
drive reward seeking. ‘How much a rat thinks the outcome of his
actions is worth’
Reduction
in
responding
without ever experiencing the
incentive value change.
120
100
80
60
40
20
0
Hungry
Sated
Motivational State
• General Motivational Arousal
The animal’s general drive towards all rewards.
Parsing Reward: Heterogeneous Seeking-Taking Chain
with Lickometer
Seeking
Taking
Outcome Delivery
Response rate changes only
after incentive learning
Incentive Value
Response rate changes
before consumption
General Motivational Arousal
Measure licking frequency
with contact lickometer
Reward Palatability
(Balleine 1995, Corbit and Balleine 2003, Balleine and Killcross 2006)
Assessing Opioid Involvement in Reward Palatability
and Incentive Learning
Training: Heterogeneous Seeking-Taking Chain
2 hours food deprivation
Test Day 1: ½ Control group ½ Hungry group
Naloxone (1µg) or Vehicle central infusions
(BLA, NAs, VP)
Freely Administered Sucrose
How much do the hungry animals ‘like’ the outcome?
Does naloxone infused into the BLA, NAs or VP alter reward palatability?
Test Day 2: Chain Extinction Test
Same hunger state, off drug
Did the incentive value of the outcome change and does this change behavior?
Does opioid receptor blockade in BLA, NAs or VP block incentive learning?
Endogenous opioids in the NAs are important for the expression of
outcome palatability, but not assignment of incentive value
Nucleus Accumbens Shell
Licks/Second
Day 1: Intra-NAs Naloxone or Vehicle
8
7
6
5
4
3
2
1
0
*
Vehicle
*
Naloxone
Intra-NAs naloxone blocks deprivation
induced increase in outcome palatability
2hr
23hr
Extinction
Seeking % Baseline
Palatability Analysis
2hr
23hr
Day 2: Off Drug
225
200
175
150
125
100
75
50
25
0
*
Vehicle
*
Naloxone
Intra-NAs naloxone does not effect
incentive learning
Endogenous opioids in the VP are important for the expression of
outcome palatability, but not assignment of incentive value
Ventral Pallidum
Licks/Second
Day 1: Intra-VP Naloxone or Vehicle
7
6
5
4
3
2
1
0
*
Vehicle
*
Naloxone
Intra-VP naloxone blocks deprivationinduced increases in outcome palatability
2hr
23hr
Extinction
Seeking % Baseline
Palatability Analysis
Day 2: Off Drug
350
300
250
200
150
100
50
0
2hr
23hr
**
*
Vehicle
Naloxone
Intra-VP naloxone does not effect incentive
learning
Endogenous opioids in the BLA modulate the assignment of
incentive value independent from outcome palatability
Basolateral Amygdala
Palatability Analysis
Extinction
Naloxone
Intra-BLA naloxone does not affect
expression of outcome palatability
350
300
250
200
150
100
50
0
Vehicle
Naloxone/
Naloxone
Vehicle
*
Vehicle/
Naloxone
*
Naloxone/
Vehicle
7
6
5
4
3
2
1
0
Day 2: On
Off Drug
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*
* Incentive
*** **
*
Learning
Vehicle/
Vehicle
Licks/Second
2hr
23hr
Seeking % Baseline
Day 1: Intra-BLA Naloxone or Vehicle
Naloxone
Blockade of opioid receptors in the BLA
blocks encoding of incentive value
Re-exposure Drug/Test Drug
Blockade of opioid receptors in the BLA
does not affect the retrieval of incentive
value
Role of Endogenous Opioids in Goal-Directed Reward Seeking
• Reward palatability and outcome-specific incentive value
are dissociable and independent aspects of goaldirected behavior
• Reward palatability and outcome-specific incentive value
require opioid receptors
• Opioid receptors in the VP and NAs are important for
expression of reward palatability, but not for incentive
value
• Opioid receptors in the BLA are important for encoding,
but not retrieving incentive value independent of reward
palatability
Goal-Directed v Habitual Behavior
Goal-directed Actions
Habitual Responses
Reward Value-Dependent
Action-Outcome Learning
Reward Value-Independent
Stimulus-Response Learning
Devalue
Endogenous Opioid
Peptides are involved in
Reward Value
Does endogenous opioid disruption prevent action control
by reward value and force habitual responding?
Producing and Testing for Goal-Directed or Habitual
Behavior
Over-trained Context
Low-Trained Context
500 Action-Outcome
50 Action-Outcome
Naloxone/
Vehicle
Test (off drug)
OR
Does endogenous opioid
blockade during learning alter
goal-directed learning and
force habitual responses?
Response Rate % Baseline
Blockade of Opioid Receptors during Training Mimics
Overtraining: Produces Habitual Behavior
30
*
20
10
0
Non Dev
Non Dev
Vehicle
Over-trained
Context
Non Dev
Naloxone
Low-Trained
Context
Within-Subjects Rats show Goal-Directed behavior in one
Context and Habitual Behavior in Naloxone-Paired Context
Test
OR
Vehicle
Naloxone
30
20
10
0
Non Dev
Vehicle
Non Dev
Naloxone
Acute Drug On Test
Response Rate % Baseline
Response Rate % Baseline
Is opioid blockade-induced habitual behavior context specific?
Vehicle
Context
Naloxone
Does immediate
opioid
receptor blockade
induceContext
habitual
20
40
behavior?
**
*
15
10
5
0
Non Dev
Vehicle
Non Dev
Naloxone
Acute Drug On Test
Conclusions
• Intact endogenous opioid system is necessary for normal
goal-directed learning
– Endogenous opioids in the VP and NAs important for expression of
palatability, but not reward seeking
– Endogenous opioids in the BLA important for the encoding, but not
the retrieval of incentive value, independent from palatability
• Blockade of opioid receptors during learning results in
inability of actions to be modulated by negative changes in
outcome value
• Potential mechanism by which drugs of abuse may, by
compromising the endogenous opioid system, render drug
seeking actions inflexible to the value of their outcome
Acknowledgements
• Dr. Nigel Maidment
• Dr. Bernard Balleine
• Dr. Sean Ostlund
• Dr. Robert Brown
• Dr. Neil Winterbauer
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***Ingrid Cely***
Matt Maga
Hoa Lam
Larry Ackerson