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

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 Addiction Compulsive Drug Use Intensive Drug Use Casual Drug Use Experimental Drug Use Circumstantial Drug Use Motivational Strength 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

Choice Behavior and the Notion of “Self-Control” Response Selection Behavior foodsexsocialdrug

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

Motivational Toxicity Producing a Self-Perceived “Loss of Control” Response Selection Behavior foodsexsocialdrug

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 Broekkamp et al., 1975 IVSA/NAS dopamine-depleting lesions Lyness et al., 1979 Roberts et al., 1977, 1980 IVSA/VTA dopamine-depleting lesions Roberts & Koob, 1982 IVSA/NAS kainic acid lesions Zito et al., 1985 ICSA/NAS amphetamine Hoebel et al., 1983 CPP/NAS amphetamine microinjections White et al., this volume CPP/NAS dopamine-depleting lesions Spyraki et al., 1982 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  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 A 10 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 BSR CPP IVSA ICSA Models are not required to fit all of the data but only to be the best fit for most of data. Convergent operations are critically important. Old models are replaced when better models become available.

Brain Reward Circuitry From Bozarth, 1987.

Psychomotor Stimulant Link in Brain Reward Circuitry From NIDA “Mind Over Matter,” From Bozarth, 1987.

Opiate Link in Brain Reward Circuitry From Scientific American Medicine Online, 2000.From Bozarth, 1987.

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 From Bozarth, Pudiak, & KuoLee, 1997.

Dose-Response Analysis of BSR Facilitation Produced by Various Substances Note: The maximum facilitation seen at any time after injection is shown for each compound. From Bozarth, Pudiak, & KuoLee, 1997.

A Comparison of the Effects of Cocaine and Mildly Psychoactive Substances on BSR From Bozarth, Pudiak, & KuoLee, 1997.

A Quantitative Comparison of the Effects of Cocaine and Nicotine on BSR 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 pre- existing condition necessary for cross-sensitization or priming-like effects –a hypoactive dopamine system would provide the pre- existing 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 anhedoniacraving Chronic hypodopaminergic activity Transitory hyperdopaminergic activity Motivational Toxicity Dependent Relapse

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.