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 4 th Annual Drug Abuse Research Symposium September 26 th 2008 Endogenous Opioid Regulation of Goal-Directed and Habitual Behavior

NAcNAs DMSDLS PFC VTA VP CeN MDT Incentive Value Opioid Receptors How and Where are Opioid Receptors Involved in Goal-Directed Behavior? 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? BLA

Parsing Reward during Goal-Directed Instrumental Behavior Reduction in responding without ever experiencing the incentive value change. 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.

Parsing Reward: Heterogeneous Seeking-Taking Chain with Lickometer Seeking Response rate changes only after incentive learning Incentive Value Taking Response rate changes before consumption General Motivational Arousal Outcome Delivery 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 Test Day 1: ½ Control group ½ Hungry group Naloxone (1µg) or Vehicle central infusions (BLA, NAs, VP) Freely Administered Sucrose Test Day 2: Chain Extinction Test Same hunger state, off drug Training: Heterogeneous Seeking-Taking Chain 2 hours food deprivation How much do the hungry animals ‘like’ the outcome? Does naloxone infused into the BLA, NAs or VP alter reward palatability? 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 Intra-NAs naloxone blocks deprivation induced increase in outcome palatability Nucleus Accumbens Shell 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 Intra-VP naloxone blocks deprivation- induced increases in outcome palatability Ventral Pallidum Intra-VP naloxone does not effect incentive learning

Incentive Learning Endogenous opioids in the BLA modulate the assignment of incentive value independent from outcome palatability Basolateral Amygdala 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

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 retrieving incentive value independent of reward palatability Role of Endogenous Opioids in Goal-Directed Reward Seeking

Goal-Directed v Habitual Behavior Goal-directed Actions Reward Value-Dependent Action-Outcome Learning Habitual Responses Reward Value-Independent Stimulus-Response Learning Endogenous Opioid Peptides are involved in Reward Value Does endogenous opioid disruption prevent action control by reward value and force habitual responding? Devalue

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

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

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

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 ***Ingrid Cely*** Matt Maga Hoa Lam Larry Ackerson