Reward Mechanisms in Normal
and Pathological Behavior
–The Dopamine Link as a Target for
Therapeutic Intervention
Michael A. Bozarth, Ph.D.
Addiction Research Unit
Department of Psychology
University at Buffalo
Buffalo, NY 14260-4110
www.AddictionScience.net
The “Program”
• Concept of addiction
• Dopamine involvement in psychomotor stimulant
and opiate addiction
– development of a model reward system
• Role of organismic variables in addiction
– predisposition to addiction
– enabling addiction to mildly psychoactive substances
• Commentary on the dopamine link as a
therapeutic target
What is Addiction?
• Addiction is a behavioral syndrome where drug
procurement and use seem to dominate the
individual’s motivation and where the normal
constraints on the individual’s behavior are
generally ineffective (e.g., self-perceived “loss of
control”)
– motivational toxicity may be a defining characteristic
– physical dependence is neither a necessary nor a
sufficient condition
Continuum of Drug Use
Experimental
Drug Use
Casual
Drug Use
Intensive
Drug Use
Compulsive
Drug Use
Addiction
Motivational Strength
Circumstantial
Drug Use
Motivational Toxicity
From Bozarth (1990); terms described on the
continuum were suggested by Jaffe (1975).
Addiction as a
Motivational Problem
• Addiction is best understood by considering the
drug’s impact on the individual’s motivation
• Experimental psychology and behavioral
neuroscience provide the methods for analysis
• Model building provides the heuristics
– models as tentative ideational testing devices
– importance of convergent operations
Dynamic Feature of the
Motivational Hierarchy
"group"
"mate"
food
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Choice Behavior and
the Notion of “Self-Control”
Response Selection
food
sex
Behavior
social
drug
Motivational Toxicity
• Motivational toxicity describes a disruption of the
motivational hierarchy. This is manifest as
– increased motivational efficacy of the drug
– decreased motivational efficacy of natural rewards
• Motivational toxicity produces the intense
motivational focusing characteristic of addiction
and the apparent “enslavement” inherent in the
etymology of this term
Progressive Focusing of
Motivational Energy on Drug
week-5
week-3
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Motivational Toxicity Producing a
Self-Perceived “Loss of Control”
Response Selection
food
sex
Behavior
social
drug
Progress in Understanding the
Biological Basis of Drug Addiction
• Delineation of the effects of addictive drugs on
brain systems mediating reward and motivation
(1980s-1990s)
• Current focus
– Extension of experimental findings to human studies
– Exploration of CNS neuroadaptive effects produced by
addictive drugs
– Identification of factors that facilitate the development
of an addiction
• Clinical applications (2001 and beyond)
Evidence that Psychomotor Stimulant Reward
Involves an Action in the Nucleus Accumbens
Effect
Investigator(s)
BSR/NAS amphetamine microinjections
IVSA/NAS dopamine-depleting lesions
Broekkamp et al., 1975
Lyness et al., 1979
Roberts et al., 1977, 1980
Roberts & Koob, 1982
Zito et al., 1985
Hoebel et al., 1983
White et al., this volume
Spyraki et al., 1982
IVSA/VTA dopamine-depleting lesions
IVSA/NAS kainic acid lesions
ICSA/NAS amphetamine
CPP/NAS amphetamine microinjections
CPP/NAS dopamine-depleting lesions
From Bozarth, 1987.
Evidence that Opiate Reward Involves an
Action in the Ventral Tegmental Area
Effect
Investigator(s)
BSR/VTA morphine microinjections
Broekkamp et al., 1976
Broekkamp et al., 1979
BSR/VTA dopamine-depleting lesions
Hand & Franklin, 1985
IVSA/VTA dopamine-depleting lesions
Bozarth & Wise, 1986
IVSA/VTA narcotic antagonist microinjections
Britt & Wise, 1983
IVSA/VTA morphine reinstatement of responding Stewart, 1984
Stewart & de Wit, this volume
ICSA/VTA fentynal
van Ree & De Wied, 1980
ICSA/VTA morphine
Bozarth & Wise, 1981, 1982
CPP/VTA morphine
Bozarth & Wise, 1982
Phillips & LePiane, 1980
CPP/VTA opioid peptide
Phillips & LePiane, 1982
CPP/VTA enkephalinase inhibitor
Glimcher et al., 1984
CPP/VTA dopamine-depleting lesions
Spyraki et al., 1983
From Bozarth, 1987.
Evidence for a Common Reward Substrate:
Convergent Operations-1975-1985
• No fewer than 9 independent studies had established
the role of the nucleus accumbens dopamine terminal
field in psychomotor stimulant reward
• No fewer than 15 independent studies had established
the role of the ventral tegmental area (origin of the A10
dopamine system) in opiate reward
• Replication and extension of these findings continued
throughout the next decade providing strong
corroborating evidence for the proposed model
Scientific Model Building:
Heuristics & Convergent Operations
Models are not required
to fit all of the data but
only to be the best fit for
most of data.
IVSA
BSR
CPP
ICSA
Old models are replaced when
better models become available.
Convergent operations
are critically important.
Brain Reward Circuitry
From Bozarth, 1987.
Psychomotor Stimulant Link in
Brain Reward Circuitry
From NIDA “Mind Over Matter,” 2000.
From Bozarth, 1987.
Opiate Link in
Brain Reward Circuitry
From Bozarth, 1987.
From Scientific American Medicine Online, 2000.
Dopamine & Reward
• The reward model does not propose that
dopamine is exclusively involved in reward nor
that reward from these drugs comes entirely from
this dopamine system
• The reward model does suggest that any event that
activates this system can produce a significant (but
not necessarily addictive) rewarding effect
– at least two pharmacologically distinct classes of
addictive drugs derive a major part of their rewarding
effects by their actions on this brain reward system
Possible Action of Other Substances
on Brain Reward Circuitry
Psychomotor Stimulants
Caffeine
Pseudoephedrine
Opiates
Barbiturates
Nicotine
Phencyclidine
Ethanol?
Experimental Preparation to Study
Rewarding Effects of Electrical
Brain Stimulation
From Reid, 1987.
Effect of Cocaine on Brain Reward Systems
as Measured by Brain Stimulation Reward
120
% Baseline Threshold
110
100
90
80
70
60
50
saline
1.25 mg cocaine
2.5 mg cocaine
5 mg cocaine
10 mg cocaine
20 mg cocaine
40
30
20
10
0
15
30
45
60
75
90 105 120 135 150 165 180
Minutes Post Injection
From Bozarth, Pudiak,
& KuoLee, 1997.
Dose-Response Analysis of BSR Facilitation
Produced by Various Substances
Relative Potencies of Various Compounds
% Threshold Lowering
80
nicotine
pseudoephedrine
cocaine
caffeine
diphenhydramine
tripelennamine
70
60
50
40
30
20
10
0
0.3
Note: The maximum facilitation seen at any time
after injection is shown for each compound.
1
3
10
30
Dose (moles/kg)
100
300
From Bozarth, Pudiak,
& KuoLee, 1997.
A Comparison of the Effects of Cocaine and
Mildly Psychoactive Substances on BSR
% Threshold Lowering
80
70
60
50
40
30
20
10
0
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aff
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From Bozarth, Pudiak,
& KuoLee, 1997.
A Quantitative Comparison of the Effects of
Cocaine and Nicotine on BSR
% Baseline Threshold
140
120
100
80
60
40
20
0
cocaine
nicotine
From Bozarth, unpublished
observations, 1997.
A Substance’s Addiction Liability
versus Addiction to a Substance
• The case of nicotine is particularly problematic for
models attributing addiction to a simple
pharmacological activation of brain reward systems
– obviously numerous cases of addiction-like tobacco use exist
– nicotine’s action of “normal” brain reward systems is too weak to
motivate this behavior
• Organismic variables must be important in
“enabling” apparent addiction to nicotine
– psychological stress
– abnormalities in brain reward systems
Revised Role of the Mesolimbic
Dopamine System in Drug Addiction
• Activation provides positive reinforcement and
maintains initial drug use
• Neuroadaptive changes produce . . .
– negative reinforcement (normalization)
– enhanced positive reinforcement (sensitization)
– motivational toxicity (derived process)
• Simple activation of this dopamine system is not
sufficient to produce addiction
• Organismic variables can significantly modify the
motivational impact of various rewards
Importance of Neuroadaptive
Effects in Drug Addiction
• Drug-induced neuroadaptive effects may
distinguish the normal influence this brain reward
system has on behavior from the extreme control
characteristic of drug addiction
• Events that activate this system without producing
neuroadaptive changes may lack the ability to
produce an addiction in “normal” subjects
• Neuroadaptive effects may be less important in
individuals with pre-existing abnormalities in
reward function
Modulation of Drug Reward
• Events known to enhance reward from
psychomotor stimulants and/or opiates
– exposure to some drugs
• highly addictive drugs (e.g., psychomotor stimulants, opiates)
• mildly psychoactive substances (e.g., caffeine? nicotine?)
– psychological stress (i.e., uncontrollable)
– pharmacological manipulation of dopamine systems
• chronic neuroleptic treatment accompanying schizophrenia
– genetic differences in brain dopamine function
Dopamine Activity &
Predisposition to Addiction
• Which condition increases addiction risk?
Too much or too little dopamine activity?
• Either one!
• Abnormally high or low dopaminergic activity
may mimic the individual components of
motivational toxicity
– hyperdopaminergic activity may increase the
motivational impact of drug reward
– hypodopaminergic activity may diminish the
motivational impact of ‘natural’ rewards
Implications of Abnormal
Dopamine Function
• Subjects with abnormal dopaminergic function
may become “addicted” to events which produce
minimal neuroadaptive changes or that produce
only moderate activation of this reward system
– a hyperactive dopamine system would provide the preexisting condition necessary for cross-sensitization or
priming-like effects
– a hypoactive dopamine system would provide the preexisting condition necessary for a positive contrast-like
effect
The “Exposure” View of Addiction
(Revisited)
• Addiction is ultimately pharmacologically
determined
– the result of the action of certain drugs on brain reward
mechanisms
• Several factors can
– hasten the development of an addiction
– make certain individuals more likely to develop an
addiction
– enable addiction to some substances and events that are
not considered “addictive” for the general population
Some Possible Predisposing and
Enabling Factors for Drug Addiction
• Psychological stress
• Drug exposure
• Genetic abnormalities
Relapse to Drug Use
Motivational Toxicity
Dependent Relapse
Chronic
hypodopaminergic
activity
anhedonia
Transitory
hyperdopaminergic
activity
craving
The Dopamine Link as a Possible
Target for Therapeutic Intervention
• Abnormalities in brain dopamine function may
identify individuals with a high risk for addiction
• Direct manipulation of dopaminergic function is
unlikely to prove successful in treating addiction
– addiction probably involves neuroadaptive effects and
not just simple activation of dopamine systems
– modification of dopaminergic action is likely to have
global effects on motivation, affect, and behavior
• Systems modulating dopaminergic activity are
more viable targets for therapeutic intervention
Beyond Dopamine Agonist &
Antagonist Treatments
• Orthomolecular psychiatry
– precursor loading
– macronutrient manipulation
• Autoreceptor regulation
• Other regulatory systems
–
–
–
–
–
5-HT
GABA
endogenous opioid peptides
NMDA
NO
A Psychobiological Model of
Drug Addiction
From Bozarth, 1990.