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

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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

Pleasant Unpleasant Neutral

Perception of Methylphenidate

Bm

ax/K

d

3.8

2.8

2.6

2.4

2.2

3.6

3.4

3.2

3.0

Volkow et al. (1999)

[11C

] R

aclo

pri

de

3.02.82.62.42.22.00.00

0.05

0.10

0.15

0.20

Week 5

Baseline D2 DVR

r = - 0.86

Res

po

nse

Rat

e (

resp

on

ses

/ se

c)

Nader et al. (2006)

Inverse Relationship between D2 Availability and Reinforcement

Types of Animal Models

II. Isomorphic

I. Predictive

III. Homologous

• Resembles the disease in terms of etiology, symptomatology, and predictive outcome.

• Does not resemble the disease in terms of etiology or symptomatology, but is predictive of clinical outcome.

• Resembles the disease in terms of symptoms and predictive outcome, but is artificially produced in the lab.

Trait Variable - a distinguishable characteristic of one’s personal nature.

Genetic vs. Environmental Modulation

State Variable - a distinguishable characteristic attributable to environmental circumstances.

Vulnerability

Maintenance

Abstinence

Modeling Addiction: Trait vs. State Variables

• 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

Social Rank

Based on the outcomes of agonistic encounters (i.e. fights)

12

34

MostDominant

MostSubordinate

Individually-housed (n=20)

PET imaging Hormonal profiles Locomotor reactivity

PET imaging Hormonal profiles Social behavior

Cocaine self-administration

Socially-housed (n=4/group)

Vulnerability to Cocaine Use

What are some of the neurobiological, neuroendocrine and behavioral predictors and consequences of cocaine use?

PET imaging

Lo

co

mo

t or

Co

un

ts1 2 3 4

0

200

400

600

800

1000

Social Rank

SalineCocaine

Morgan et al. (2000) Am J Primatol 52: 115-131

Locomotor Reactivity

Dominant

Subordinate

IndividuallyHoused

SociallyHoused

Morgan et al. (2002) Nature Neuroscience 5: 169-174

Dominant

Subordinate

IndividuallyHoused

SociallyHoused

Morgan et al. (2002) Nature Neuroscience 5: 169-174

**

S.003 .01 .03 .1

0

10

20

30

40

50

REINFORCERS(per session)

Cocaine (mg/kg/injection)

Environmental Variables, Brain Function and Cocaine Abuse

Subordinate

Dominant

Vulnerable

Protected

DA; D2 density

DA; D2 densityEnriched

Stressed

Female Cynomolgus Monkeys

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

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

Con

cent

ratio

n (n

g/m

l)

Impulsivity and CSF Metabolite Levels

Vulnerability

Maintenance

Abstinence

Modeling Addiction: Trait vs. State Variables

• 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

After 2-5 years of cocaine self-administration …

Czoty et al. (2004) Psychopharmacology 174: 381-388

2.0

0.0

0.5

1.0

1.5

0.003 0.01 0.03 0.1

Cocaine (mg/kg/injection)

Co

cain

e In

take

(m

g/k

g)

DominantIntermediateSubordinate

After 2-5 years of cocaine self-administration …

Czoty et al. (2004) Psychopharmacology 174: 381-388

2.0

0.0

0.5

1.0

1.5

0.003 0.01 0.03 0.1

Cocaine (mg/kg/injection)

Co

cain

e In

take

(m

g/k

g)

DominantIntermediateSubordinate

dominant

subordinate

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)

5 10 15

0

25

50

75

100

125

5 10 15

0

25

50

75

100

125 Surbordinate MonkeysDominant Monkeys

Surbordinate Monkeys Self-Administering

Dominant Monkeys Self-Administering

5 10 15

0

25

50

75

100

125

5 10 15

0

25

50

75

100

125 Surbordinate MonkeysDominant Monkeys

5 Minute Blocks5 Minute Blocks

Ag

gre

ssio

n S

core

s(s

um

s)

Ag

gre

ssio

n S

core

s(s

um

s)

BaselineCocaine 0.01Cocaine 0.03Cocaine 0.1

Ag

gre

ssio

n S

core

s(s

um

s)

Ag

gre

ssio

n S

core

s(s

um

s)

5 Minute Blocks5 Minute Blocks

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

Cocaine choice in socially housed monkeys

S

0

20

40

60

80

100

0.003 0.01 0.03 0.1

dominant

subordinate

*

Cocaine (mg/kg per injection)Czoty et al. (2005) JPET 312: 96-102

Vulnerability

Maintenance

Abstinence

Modeling Addiction: Trait vs. State Variables

• 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

Recovery of rank-related differences during abstinence from cocaine

DominantIntermediateSubordinate

[18F

]FC

P D

VR

D I S D I S D I S

1.0

1.5

2.0

2.5

3.0

3.5

CAUDATE PUTAMEN ANT CNG CTX

*

4 Dominant 4 Subordinate 4 Intermediate

4 Intermediate2 Intermediate

2 Naive4 Naïve

What’s next? Social reorganization:Can changes in the environment produce changes in D2 receptors and cocaine reinforcement?

Measures of “impulsivity”Cortisol levels

Social Reorganization

What are some of the predictors of social rank?

Cortisol levelsSocial behaviorPET imagingCocaine self-administration

What are some of the consequences of the new social rank?

less

moreimpulsive

Latency to touch

1 2 3 4

0

100

200

300

400900

Eventual Rank

“Impulsivity” did not predict eventual social rank

(sec)

less

moreimpulsive

Latency to touch

1 2 3 4

0

100

200

300

400900

Eventual Rank

“Impulsivity” did not predict eventual social rank,but was related to previous social rank.

PREVIOUS rank

1

2

Individually housed

(sec)

Basal cortisol levels do not predict eventual rank

Pen D

0

5

10

15

20

25

30

35

Squeaky (3)

Kramer (2)

Gumby (4)

Rusty (1)

Time of Day7:00AM or 4:30PM

Pen F

0

5

10

15

20

25

30

35

Escobar (1)

Heath (2)

LJ (3)

Seamus (4)

Time of Day7:00AM or 4:30PM

Group data:Eventual rank a.m. p.m. 1 23.8 ± 2.2 14.8 ± 2.4 2 20.0 ± 1.2 11.7 ± 1.9 3 22.2 ± 2.7 11.7 ± 3.0 4 20.4 ± 2.2 10.6 ± 2.4

Diurnal cortisol fluctuations prior to social housing

pm am pm am pm am

50

100

150

200

250

300

350 1

2

3

4

DAY: 1 2 3 4

Cortisol levels during initial social housing

Monkeys were individually housed overnight, group housed during the day.

n = 6 @ each rank

Social reorganization- determining hierarchy

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

----

Rank 1 2 3 4

1

2

3

4

----

4.9

10.6

14.7

0.1

----

3.9

9.2

0.0

0.1

----

19.8

0.0

0.0

0.2

----

Rank 1 2 3 4

Aggressive Submissive

n = 6 @ each rank

Received Received

Init

iate

d

Init

iate

d

Average Actions/hour

D2 receptor availability in “reorganized” monkeys

1 2 3 4 1 2 3 4

1

2

3

4

caudate putamen

rank

individual subject data

Cocaine choice in “reorganized” monkeys

individual subject data

0.01 0.1 10.003 0.03 0.3

0

20

40

60

80

100 1234

cocaine (mg/kg per injection)

Influence of environmental variables on the brain and behavior

persists, but may be influenced by social housing and/or drug history.

Previously dominant monkeys

0.01 0.1 10.003 0.03 0.3

0

20

40

60

80

100

123

currentrank:

4

cocaine (mg/kg per injection)

Previously subordinate monkeys

0.01 0.1 10.003 0.03 0.3

0

20

40

60

80

100

cocaine (mg/kg per injection)

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 .

The environment exerts profound effects on brain function that can impact clinical outcomes.

SUMMARY

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.

Acknowledgments

Drake MorganCiara McCabeMatthew DickensCliff HubbardOsric PrioleauJennifer SandridgeAmy Young

Kim BlackMichael BoundsNancy BuchheimerRichard EhrenkauferH. Donald GagePradeep GargKathleen GrantRobert H. MachBeth Reboussin

National Institute on Drug Abuse

DA 10584DA 17763