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

4. Types of Animal Models I. Predictive II. Isomorphic III. Homologous
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. Locomotor Reactivity Saline Cocaine Social Rank L o c m t r C u n s 12 3 4
200
400
600
800
1000
Social Rank
Saline
Cocaine
Morgan et al. (2000) Am J Primatol 52:

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

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

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

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

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

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

18. Interactions of cocaine reinforcement with social behavior
Methods
Cocaine (saline, 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. Dominant Monkeys Self-Administering
125
Surbordinate Monkeys
125
100
100
Baseline
Cocaine 0.01
Cocaine 0.03
Cocaine 0.1
Aggression Scores
(sums) 75
Aggression Scores
(sums) 75 50 50 25 25 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 5 10 15 5 10 15
5 Minute Blocks
5 Minute Blocks

20. Issues Related to Decision Making in 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:

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 .
[18F]FCP DVR 2 . 5 2 . 1 . 5 1 . D I S D I S D I S C A U D A T E P U T A M E N A N T C N G C T X

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

27. “Impulsivity” did not predict eventual social rank,
(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 rank a.m p.m.
± ± 2.4
± ± 1.9
± ± 3.0
± ± 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 = each rank

30. Social reorganization- determining hierarchy
Average Actions/hour
Aggressive
Submissive
Received
Received
Rank
Rank 1 2 3 4
----
0.3
0.2
0.2
1.3
----
0.3
0.2
1.3
3.7
----
0.3 
5.5
5.3
13.0
---- 1 2 3 4
----
4.9
10.6
14.7
0.1
----
3.9
9.2
0.0
0.1
----
19.8 
0.0
0.2
----
Initiated
Initiated
n = 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. National Institute on Drug Abuse
Acknowledgments
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
National Institute on Drug Abuse
DA 10584
DA 17763