OUTLINE

1. Social Behavior of Nonhuman Primates: Effects on Brain Dopamine Systems and on Cocaine Reinforcement Michael A. Nader, Paul W. Czoty, Susan H. Nader, Robert Gould, Michelle Icenhower, Natallia Riddick and Jay R. Kaplan

2. OUTLINE 1. Factors that predict social rank in male and female cynomolgus monkeys Body weight, locomotor activity, hormone levels, receptor availability 2. Variables that change as a consequence of social group formation Dopamine D2 receptor availability, cocaine self-administration 3. Variables that are affected by abstinence and social re-organization Dopamine D2 receptor availability, cocaine self-administration

3. 0.20 3.8 Nader et al. (2006) Volkow et al. (1999) 3.6 0.15 Week 5 r = - 0.86 3.4 3.2 [11C] Raclopride Bmax/Kd 0.10 Response Rate (responses/ sec) 3.0 2.8 0.05 2.6 2.4 0.00 2.2 2.0 2.2 2.4 2.6 2.8 3.0 Pleasant Unpleasant Neutral Perception of Methylphenidate Baseline D2 DVR Inverse Relationship between D2 Availability and Reinforcement

4. Types of Animal Models I. Predictive • Does not resemble the disease in terms of etiology or symptomatology, but is predictive of clinical outcome. II. Isomorphic • Resembles the disease in terms of symptoms and predictive outcome, but is artificially produced in the lab. III. Homologous • Resembles the disease in terms of etiology, symptomatology, and predictive outcome.

5. Genetic vs. Environmental Modulation Trait Variable - a distinguishable characteristic of one’s personal nature. State Variable - a distinguishable characteristic attributable to environmental circumstances.

6. Modeling Addiction:Trait vs. State Variables Vulnerability Maintenance Abstinence • genetic or environmental factors • mediating predisposition during • early exposure • behavioral & neurobiological • consequences of repeated use • recovery of cocaine-induced changes • long-term changes that influence • relapse

7. Social Rank Based on the outcomes of agonistic encounters (i.e. fights) 1 2 Most Dominant Most Subordinate 3 4

8. Vulnerability to Cocaine Use What are some of the neurobiological, neuroendocrine and behavioral predictors and consequences of cocaine use? Individually-housed (n=20) PET imaging Hormonal profiles Locomotor reactivity Socially-housed (n=4/group) PET imaging Hormonal profiles Social behavior Cocaine self-administration PET imaging

9. 1000 Saline Cocaine 800 s t n u o 600 C r o t o 400 m o c o L 200 0 1 2 3 4 Social Rank Locomotor Reactivity Morgan et al. (2000) Am J Primatol 52: 115-131

10. Individually Housed Socially Housed Dominant Subordinate Morgan et al. (2002) Nature Neuroscience 5: 169-174

11. Individually Housed Socially Housed REINFORCERS (per session) 50 40 * 30 * Dominant 20 10 0 S .003 .01 .03 .1 Cocaine (mg/kg/injection) Subordinate Morgan et al. (2002) Nature Neuroscience 5: 169-174

12. Environmental Variables, Brain Function and Cocaine Abuse Dominant Protected DA; D2 density Enriched Subordinate Vulnerable DA; D2 density Stressed

13. Behavioral measures Locomotor activity Impulsivity, novel object PET [18F]FCP [18F]FCT [11C]DASB CSF 5-HIAA, HVA, 5-HT Socially housed n=4/pen Female Cynomolgus Monkeys Individually housed n=16 Behavioral measures • Social behavior • 5-HT drugs PET • [18F]FCP • [18F]FCT • [11C]DASB CSF • 5-HIAA, HVA, 5-HT Cocaine self-administration

14. Impulsivity and CSF Metabolite Levels Concentration (ng/ml)

15. Modeling Addiction:Trait vs. State Variables Vulnerability Maintenance Abstinence • genetic or environmental factors • mediating predisposition during • early exposure • behavioral & neurobiological • consequences of repeated use • recovery of cocaine-induced changes • long-term changes that influence • relapse

16. 2.0 Dominant Intermediate 1.5 Subordinate Cocaine Intake (mg/kg) 1.0 0.5 0.0 0.003 0.01 0.03 0.1 Cocaine (mg/kg/injection) After 2-5 years of cocaine self-administration … Czoty et al. (2004) Psychopharmacology 174: 381-388

17. subordinate After 2-5 years of cocaine self-administration … 2.0 Dominant dominant Intermediate 1.5 Subordinate Cocaine Intake (mg/kg) 1.0 0.5 0.0 0.003 0.01 0.03 0.1 Cocaine (mg/kg/injection) Czoty et al. (2004) Psychopharmacology 174: 381-388

18. Interactions of cocaine reinforcement with social behavior • Methods • Cocaine (saline, 0.03-0.3 mg/kg/inj) dose-response curve determined. Only one monkey per social group self-administered cocaine (Mon-Fri). • Dependent variables: • (a) response rates as a function of dose • (b) social behavior (aggression, affiliation)

19. Baseline Cocaine 0.01 Cocaine 0.03 Cocaine 0.1 Dominant Monkeys Self-Administering Dominant Monkeys 125 Surbordinate Monkeys 125 100 100 Aggression Scores (sums) 75 75 Aggression Scores (sums) 50 50 25 25 0 0 5 10 15 5 10 15 5 Minute Blocks 5 Minute Blocks Surbordinate Monkeys Self-Administering Dominant Monkeys Surbordinate Monkeys 125 125 100 100 Aggression Scores (sums) Aggression Scores (sums) 75 75 50 50 25 25 0 0 5 10 15 5 10 15 5 Minute Blocks 5 Minute Blocks

20. Issues Related to Decision Making in Cocaine Abusers • Cocaine abusers: • make poor decisions • are highly impulsive • over-value cocaine relative to other reinforcing activities • Single-lever self-administration procedures do not take into account the aspect of choice • Solution: concurrent (simultaneous) availability of cocaine and another reinforcer

21. Cocaine choice in socially housed monkeys Czoty et al. (2005) JPET 312: 96-102

22. Modeling Addiction:Trait vs. State Variables Vulnerability Maintenance Abstinence • genetic or environmental factors • mediating predisposition during • early exposure • behavioral & neurobiological • consequences of repeated use • recovery of cocaine-induced changes • long-term changes that influence • relapse

23. Recovery of rank-related differences during abstinence from cocaine * 3 . 5 Dominant Intermediate Subordinate 3 . 0 [18F]FCP DVR 2 . 5 2 . 0 1 . 5 1 . 0 D I S D I S D I S P U T A M E N A N T C N G C T X C A U D A T E

24. What’s next? Social reorganization: Can changes in the environment produce changes in D2 receptors and cocaine reinforcement? 4 Dominant 4 Subordinate 4 Intermediate 4 Intermediate 2 Intermediate 2 Naive 4 Naïve

25. Social Reorganization What are some of the predictors of social rank? Measures of “impulsivity” Cortisol levels What are some of the consequences of the new social rank? Cortisol levels Social behavior PET imaging Cocaine self-administration

26. (sec) less more impulsive “Impulsivity” did not predict eventual social rank

27. (sec) PREVIOUS rank less 1 2 Individually housed more impulsive “Impulsivity” did not predict eventual social rank, but was related to previous social rank.

28. Diurnal cortisol fluctuations prior to social housing Group data: Eventual ranka.m.p.m. 123.8 ± 2.2 14.8 ± 2.4 220.0 ± 1.2 11.7 ± 1.9 322.2 ± 2.7 11.7 ± 3.0 420.4 ± 2.2 10.6 ± 2.4 Basal cortisol levels do not predict eventual rank

29. Cortisol levels during initial social housing Monkeys were individually housed overnight, group housed during the day. n = 6 @ each rank

30. Social reorganization- determining hierarchy Average Actions/hour Aggressive Submissive Received Received Rank 1 2 3 4 Rank 1 2 3 4 1.3 ---- 0.3 0.2 1 2 3 4 0.1 ---- 3.9 9.2 1 2 3 4 ---- 0.3 0.2 0.2 1.3 3.7 ---- 0.3 ---- 4.9 10.6 14.7 0.0 0.1 ---- 19.8 5.5 5.3 13.0 ---- 0.0 0.0 0.2 ---- Initiated Initiated n = 6 @ each rank

31. D2 receptor availability in “reorganized” monkeys individual subject data rank

32. Cocaine choice in “reorganized” monkeys individual subject data

33. Influence of environmental variables on the brain and behavior persists, but may be influenced by social housing and/or drug history.

34. SUMMARY • The combination of nonhuman primate social behavior, models of drug abuse, behavioral pharmacology and noninvasive brain imaging techniques has provided important evidence regarding: • the neurobiological basis of vulnerability to addictive effects of drugs. D2 receptors and social rank; CSF and impulsivity. • the influence of environmental variables on brain function and behavior. Social rank and drug choice. • neurobiological changes produced by long-term drug use, abstinence and reorganization. An interaction between previous social rank and current conditions on D2 receptors and cocaine reinforcement .

35. SUMMARY The environment exerts profound effects on brain function that can impact clinical outcomes. O’Brien and Anthony (2005): education has an inverse relationship with risk of becoming cocaine dependent. Butzin et al. (2005): work release programs for inmates resulted in greater abstinence rates and higher rates of employment after leaving the program. Daniel et al. (2006): exercise reduces desire to smoke cigarettes and reduces withdrawal symptoms. Winkelman (2003): percussion instruments (drums) during treatment. Music reduces stress, is reinforcing, enhances awareness and alleviates isolation.

36. Drake Morgan Ciara McCabe Matthew Dickens Cliff Hubbard Osric Prioleau Jennifer Sandridge Amy Young Kim Black Michael Bounds Nancy Buchheimer Richard Ehrenkaufer H. Donald Gage Pradeep Garg Kathleen Grant Robert H. Mach Beth Reboussin Acknowledgments National Institute on Drug Abuse DA 10584 DA 17763