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![Page 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.](https://reader036.fdocuments.net/reader036/viewer/2022062803/56649f525503460f94c76edd/html5/thumbnails/1.jpg)
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
QuickTime™ and aPhoto - JPEG decompressor
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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
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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
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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.
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Trait Variable - a distinguishable characteristic of one’s personal nature.
Genetic vs. Environmental Modulation
State Variable - a distinguishable characteristic attributable to environmental circumstances.
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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
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Social Rank
Based on the outcomes of agonistic encounters (i.e. fights)
12
34
MostDominant
MostSubordinate
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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
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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
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Dominant
Subordinate
IndividuallyHoused
SociallyHoused
Morgan et al. (2002) Nature Neuroscience 5: 169-174
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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)
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Environmental Variables, Brain Function and Cocaine Abuse
Subordinate
Dominant
Vulnerable
Protected
DA; D2 density
DA; D2 densityEnriched
Stressed
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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
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Con
cent
ratio
n (n
g/m
l)
Impulsivity and CSF Metabolite Levels
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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
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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
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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
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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)
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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
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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
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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
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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
![Page 23: Social Behavior of Nonhuman Primates: Effects on Brain Dopamine Systems and on Cocaine Reinforcement Michael A. Nader, Paul W. Czoty, Susan H. Nader, Robert.](https://reader036.fdocuments.net/reader036/viewer/2022062803/56649f525503460f94c76edd/html5/thumbnails/23.jpg)
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
*
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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?
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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?
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less
moreimpulsive
Latency to touch
1 2 3 4
0
100
200
300
400900
Eventual Rank
“Impulsivity” did not predict eventual social rank
(sec)
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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)
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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
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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
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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
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D2 receptor availability in “reorganized” monkeys
1 2 3 4 1 2 3 4
1
2
3
4
caudate putamen
rank
individual subject data
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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)
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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)
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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 .
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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.
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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
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