Charles Drew University of Medicine and Science 4 th Annual Drug Abuse Research Symposium

1. Endogenous Opioid Regulation of Goal-Directed and Habitual Behavior Kate M. Wassum, Ingrid C. Cely, Dr. Sean B. Ostlund, Dr. Nigel T. Maidment, Dr. Bernard W. Balleine Charles Drew University of Medicine and Science 4th Annual Drug Abuse Research Symposium September 26th 2008

2. How and Where are Opioid Receptors Involved in Goal-Directed Behavior? PFC Opioid Receptors MDT Incentive Value DMS DLS CeN 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?

3. Parsing Reward during Goal-Directed Instrumental Behavior • Reward Palatability Affective component of reward consumption. ‘Liking’ Reflected in taste reactivity or licking frequency. • Incentive Value 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’ • General Motivational Arousal The animal’s general drive towards all rewards. Reduction in responding without ever experiencing the incentive value change.

4. Parsing Reward: Heterogeneous Seeking-Taking Chain with Lickometer Outcome Delivery Measure licking frequency with contact lickometer Reward Palatability Seeking Response rate changes only after incentive learning Incentive Value Taking Response rate changes before consumption General Motivational Arousal (Balleine 1995, Corbit and Balleine 2003, Balleine and Killcross 2006)

5. 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?

6. Endogenous opioids in the NAs are important for the expression of outcome palatability, but not assignment of incentive value Nucleus Accumbens Shell Intra-NAs naloxone blocks deprivation induced increase in outcome palatability Intra-NAs naloxone does not effect incentive learning

7. Endogenous opioids in the VP are important for the expression of outcome palatability, but not assignment of incentive value Ventral Pallidum Intra-VP naloxone blocks deprivation-induced increases in outcome palatability Intra-VP naloxone does not effect incentive learning

8. Endogenous opioids in the BLA modulate the assignment of incentive value independent from outcome palatability Basolateral Amygdala Incentive Learning Intra-BLA naloxone does not affect expression of outcome palatability Blockade of opioid receptors in the BLA blocks encoding of incentive value Blockade of opioid receptors in the BLA does not affect the retrieval of incentive value

9. Role of Endogenous Opioids in Goal-Directed Reward Seeking • Reward palatability and outcome-specific incentive value are dissociable and independent aspects of goal-directed 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 retrievingincentive value independent of reward palatability

10. Goal-Directed v Habitual Behavior Goal-directed Actions Reward Value-Dependent Action-Outcome Learning Habitual Responses 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?

11. Producing and Testing for Goal-Directed or Habitual Behavior Over-trained Context 500 Action-Outcome Low-Trained Context 50 Action-Outcome Naloxone/ Vehicle Test (off drug) OR Does endogenous opioid blockade during learning alter goal-directed learning and force habitual responses?

12. Blockade of Opioid Receptors during Training Mimics Overtraining: Produces Habitual Behavior

13. Within-Subjects Rats show Goal-Directed behavior in one Context and Habitual Behavior in Naloxone-Paired Context Test OR Vehicle Naloxone Is opioid blockade-induced habitual behavior context specific? Does immediate opioid receptor blockade induce habitual behavior?

14. 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

15. Acknowledgements • Dr. Nigel Maidment • Dr. Bernard Balleine • Dr. Sean Ostlund • Dr. Robert Brown • Dr. Neil Winterbauer • ***Ingrid Cely*** • Matt Maga • Hoa Lam • Larry Ackerson