Foundations and Innovations in the Neuroscience of Addiction

United States

Dedicated to the memory of Dr. Roger Brown, Associate Director of Neuroscience and Behavioral Research at the National Institute on Drug Abuse

Roger Brown Memorial

Roger Brown, Ph.D.

Dr. Roger M. Brown joined the National Institute on Drug Abuse with prior training as both a pharmacist and a research neuropsychopharmacologist, and served a key role in building the foundations of a strong neuroscience research program at NIDA. Roger earned his Ph.D. under Dr. Lewis Seiden at the University of Chicago in 1972 and was especially proud of the research he accomplished during 2 years of training at the Farmakologiska Institute, Goteborg, Sweden, in the laboratory of Dr. Arvid Carlsson. Upon his return to the states, he joined the neuropsychology laboratory of Dr. Patricia Goldman-Rakic at the NIMH Intramural Research Program as a Senior Staff Fellow, and subsequently moved to NIDA in 1979 as a staff pharmacologist. At NIDA, he served as Program Official (1979-1984), Executive Secretary in the Office of Extramural Review (1981), and Chief of the Neuroscience Research Branch in the Division of Basic Research (1983-2000). In 2000, he began his tenure as the Associate Director for Neuroscience in the Division of Neuroscience and Behavioral Research, a position he held until his death in June of 2002. He was a member of the Society for Neuroscience, the American College of Neuropsychopharmacology, and the College on Problems of Drug Dependence. Roger was particularly proud of his early role in recognizing the importance of central dopaminergic systems in drug abuse and in fostering the growth and expansion of cutting-edge research that serves as the foundation of neuroscientific approaches to drug abuse and addiction today. In 2001, he received the J. Michael Morrison Award from the College on Problems of Drug Dependence in recognition of his outstanding administrative skills and leadership.

Welcome from the NIDA Director

Dear Colleagues:

It is my privilege to welcome you on behalf of the National Institute on Drug Abuse (NIDA) to this landmark conference to remember and honor the accomplishments of one of NIDA's esteemed colleagues, Dr. Roger M. Brown, Associate Director of Neuroscience and Behavioral Research.

Although Dr. Brown passed away on June 13, 2002 his neuroscience achievements live on. This symposium, "Foundations and Innovations in the Neuroscience of Addiction" and the topics to be discussed over the next two days allude to some of the exciting research programs that Roger helped foster in his more than two decades at NIDA. As a pharmacist and a research neuropharmacologist, Roger's scientific interests were diverse and wide-ranging, as reflected in this program agenda. Topics ranging from the neurotoxicity engendered by drugs of abuse, to cognitive and integrative neuroscience, to the study of mechanisms underlying pain, and the concepts of reward, both natural and drug-induced, as well as Roger's commitment to the development of the dopamine hypothesis of addiction, are all important and long-standing areas of interest that NIDA continues to support.

I am especially honored to welcome the prominent scientists, who will be sharing the latest findings in neuroscience of addiction research with us, many of whom have been supported by NIDA and have emerged as leaders in their respective areas. The opportunity to host Nobel Laureate, Dr. Arvid Carlsson, with whom Roger studied, as a keynote presenter, as well as Dr. Patricia S. Goldman-Rakic, among others, attests to the enormous strides that have been made in understanding the mechanisms that underlie addiction, while also showcasing how seemingly unrelated fields of research can come together and yield substantial advances in scientific understanding.

Despite tremendous scientific progress, much work remains to be accomplished. It is only through the innovative thinking and dedication of our researchers and program staff that we will continue to build upon the momentum that has been growing in the neuroscience arena to answer the new questions that continue to arise and to explore the new mysteries about the brain. This symposium also serves as a reminder as to what can be accomplished when we make a commitment to nurture and mentor young scientists--even more innovations can occur that will advance our understanding of the brain and thus reduce the burden of drug abuse and addiction.

In memory of our colleague, Roger Brown, and for all that he and others like him have accomplished and will continue to unveil, I welcome you.

Sincerely,
Nora D. Volkow, M.D.
Director

Videocast

• The Videocast of this meeting is available - [Videocast - Day 1] [VideoCast - Day 2].

Speaker Abstracts

LSD, Serotonin (5-HT), and the Evolution of a Behavioral Assay.
James Appel, Ph.D.

More than 25 years of research in the Behavioral Pharmacology Laboratory (University of South Carolina), which was supported by NIDA and encouraged and facilitated by Roger Brown, has indicated that serotonergic neuronal systems (5-HT2A) are involved in the discriminative stimulus effects of LSD. However, this conclusion, along with the hypothesis that substitution for LSD in rats and other animals predicts hallucinogenic potency in humans, has had to be tempered by the observation that "false-positives" sometimes occur in drug discrimination experiments; that is, administration of drugs such as lisuride, quipazine, and yohimbine, which are neither primarily serotonergic nor have LSD-like effects in humans, substitute for LSD. We have found that such false-positives can be eliminated by using training procedures that are more selective than the drug vs. no-drug procedure typically used in drug discrimination experiments; these include drug vs. drug (LSD-lisuride) and, more recently, drug vs. other drug (LSD-saline, cocaine, pentobarbital) discriminations.

Pertinent references:

1. Appel, J. B., West, W. B., Rolandi, W. G., Alici, T., and Pechersky, K. (1999). Increasing the selectivity of drug discrimination procedures. Pharmacology, Biochemistry, and Behavior, 64, 353-358.
2. Callahan, P. M., & Appel, J. B. (1990). Differentiation between the stimulus effects of LSD & lisuride using a 3-choice drug discrimination procedure. Psychopharmacology, 100, 13-18.
3. Cunningham, K. A., & Appel, J. B. (1987). Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD). Psychopharmacology, 91, 67-73.
4. White, F. J., & Appel, J. B. (1982). LSD and lisuride: Differentiation of their neuropharmacological actions. Science, 216, 535-537.

Memory, Rreward, and Substance Abuse
Sam Deadwyler, Ph.D.

The relevance of memory and reward to factors that control substance abuse is becoming more obvious as research drives toward an understanding of how these two factors operate in the brain. The research supported and fostered by Roger Brown, Ph.D., provided much of the impetus for understanding how these processes become usurped in cases of drug addiction and abuse. Current insights into the actions of abused substances, such as marijuana and cocaine, on memory and reward will be presented.

Neurochemical and Behavioral Studies on Ethanol and Nicotine interactions
J.A. Engel, M.D., Ph.D.

Ample evidence has accumulated indicating that dopamine (DA) is implicated in the brain reward systems and that DA is directly or indirectly involved in the acute reinforcing actions of ethanol, although other neurochemical systems including GABA, glutamate, serotonin, and opioid peptides also appear to participate in orchestrating the reward profile of ethanol.

The molecular events underlying the DA-enhancing properties of ethanol are largely unknown, but ethanol has been shown to directly interfere with ionic flux through several multisubunit, ligand-gated ion channels, including nicotinic acetylcholine receptors (nAChR). We have previously reported that chronic ethanol administration can produce differential Bmax changes in 3H-nicotine binding in various brain regions. We have now obtained both behavioral and neurochemical data indicating that the DA-activating and reinforcing properties of ethanol may in fact involve activation of central nAChR, especially those located in the ventral tegmental area. Studies aiming at defining the nAChR subpopulation(s) involved in mediating the effects of ethanol have revealed that the _3_2 or _6, but not the _4_2 or _7, subunits could represent targets for developing new drugs for treatment of alcoholism.

Opponent-Process Properties of Self-Administered Cocaine
Aaron Ettenberg, Ph.D.

Over the past decade, data collected in our laboratory has demonstrated that self-administered cocaine produces opponent-process-like behavioral effects. Animals running a straight alley once each day for intravenous (IV) cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This behavioral ambivalence appears to stem from concurrent rewarding and anxiogenic properties of the drug - both of which are associated with the goal box. The opponent-process actions of cocaine were more directly observed in subsequent conditioned place-preference studies where the initial immediate effects of IV cocaine were shown to be reinforcing, while the state present 15 minute postinjection was found to be aversive. In more recent work, we have shown that alcohol or heroin can reduce the negative/anxiogenic properties of cocaine and thereby account for the frequent coabuse of these compounds with cocaine.

• Ettenberg, A., Raven, M. A., Danluck, D.A., and Necessary, B.D. (1999) Evidence for opponent-process actions of intravenous cocaine. Pharmacology, Biochemistry and Behavior, 64:507-512.
• Knackstedt, L.A., Samimi, M.M. and Ettenberg, A. (2002) Evidence for opponent-process actions of intravenous cocaine and cocaethylene. Pharmacology, Biochemistry and Behavior, 72:931-936.

Neural Mechanisms of Opioid Analgesia
Howard L. Fields, M.D., Ph.D.

The pain-relieving efficacy of opioid derivatives depends on the action of a pain-modulating circuit with connections in the limbic forebrain, midbrain, and medulla. This circuit is linked by neurons that release endogenous opioids. The modulating circuit exerts bidirectional control over pain-transmitting neurons at the first central synapse. Understanding the connectivity of this circuit has provided us with profound insights into processes such as tolerance and physical dependence. In addition, research in this area has helped us to understand how psychological processes such as attention and expectancy can alter perceived pain intensity in human subjects.

Descending Modulation of Pain
Gerald F. Gebhart, Ph.D.

Experimental interest in the descending modulation of spinal cord function has a long history. Sherrington and coworkers first documented that the nociceptive flexion reflex is enhanced following spinal cord transection. Later investigations examined modulation of flexion reflexes evoked by activation of "flexion reflex afferents," which was superseded by interest in nociceptive processing in the spinal dorsal horn. The impetus for such studies arose after Reynolds reported that focal electrical stimulation in the midbrain periaqueductal gray (PAG) of the awake rat produced a profound analgesia, a finding soon reproduced in man. Subsequently, stimulation in various regions of brain has been shown to produce robust antinociception in many species, many of which coincide with sites at which microinjection of morphine produces antinociception. Compelling anatomical, electrophysiological, and pharmacological evidence has established the rostroventromedial medulla as an integral relay in descending modulation of nociception, including that elicited by PAG stimulation.

Although the principal focus of investigation has been on inhibitory modulation of spinal nociceptive processes, it has been appreciated for some time that brainstem stimulation also can enhance/facilitate spinal nociceptive processes. Ke Ren first systematically investigated the potential pronociceptive aspect of descending modulation while a student in the lab in the late 1980s. We subsequently established, with support from NIDA, that descending inhibitory and facilitatory influences were pharmacologically and anatomically distinct. It is now widely appreciated that modulation of spinal nociception from the brainstem can be facilitatory or inhibitory and accumulating evidence suggests that descending facilitatory influences may contribute to the development and maintenance of hyperalgesia following peripheral tissue inflammation. We have previously proposed that chronic pain states may be sustained by active facilitatory influences from the brainstem. Recent findings will be summarized.

Specificity of Dopamine's Actions on Working Memory Circuitry
Patricia S. Goldman-Rakic, Ph.D.

The stimulus-independent sustained activation of prefrontal neurons and their content-specific coding of information constitute the fundamental cellular basis of the brain's working memory functions. We have hypothesized that the property of persistent activity is mediated in part by recurrent excitation among pyramidal neurons in local prefrontal circuits. Evidence from work in cortical slices (Gao et al., 2001; Gao and Goldman-Rakic, 2003) and in the behaving primate (Williams and Goldman-Rakic, 1995; Constantinidis et al., 2001) will show how dopamine modulates this and other elemental neuronal interactions critical for working memory function.

References

• Constantinidis, C., Franowicz, M.N., and Goldman-Rakic, P.S. (2001) Coding specificity in cortical microcircuits: a multiple electrode analysis of primate prefrontal cortex. Journal of Neuroscience 21:3646-3655.
• Gao, W.-J., Krimer, L.S., and Goldman-Rakic, P.S. (2001) Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proceedings of the National Academy of Sciences of the United States of America 98:295-300.
• Gao, W.-J. and Goldman-Rakic, P.S. (2003) Selective modulation of excitatory and inhibitory microcircuits by dopamine. Proceedings of the National Academy of Sciences of the United States of America 100:2836-2841.
• Williams, G.V., and Goldman-Rakic, P.S. (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572-575.

Building Neural Representations of Habits
Ann Graybiel, Ph.D.

This lecture will focus on the habit system of the brain and highlight research directed towards understanding how we make and break habits. Habits are semiautomatic routines that are highly advantageous because they free us to think and attend to the world, but the habit system can also be hijacked by disease and drug exposure.

This lecture will report electrophysiological and gene-based experimental studies aimed at understanding habit formation.

Cocaine Effects on the Developing Brain: Current Status
John A. Harvey, Ph.D.

The long-term effects of in utero exposure to cocaine will be described in terms of anatomical, neurochemical, physiological, and behavioral consequences in experimental animals and compared with current findings in clinical studies. A model describing the basic mechanisms through which cocaine affects the developing brain and produces long-term behavioral deficits will be presented.

Cortico-Limbic-Striatal Circuitry and Reward Mechanisms: Insights for Addiction
Ann E. Kelley, Ph.D.

The work in this laboratory has focused on understanding the basic neurobiological mechanisms underlying appetitive motivation. Studies have focused primarily on the role of the nucleus accumbens and its associated circuitry in the control of reward learning and food intake. This endeavor has included investigations of glutamate, GABA, dopamine, and opioid systems within this network. Evidence is provided that describes a key cortico-ventral striatal-hypothalamic pathway in the control of food motivation, and a parallel pathway linked to voluntary motor circuits that controls adaptive instrumental learning. Drug-induced alterations in these brain systems mediating natural rewards may contribute to addiction.

Neurobiological Mechanisms in the Transition From Drug Use to Drug Dependence
George F. Koob, Ph.D.

Drug addiction is a chronic relapsing disorder characterized by compulsive drug intake, loss of control over intake, and impairment in social and occupational function. Animal models have been developed for various stages of the addiction cycle with a focus in our work on the motivational effects of drug dependence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework by which to identify the neurobiologic mechanisms involved in the development of drug addiction. Neuropharmacologic studies in animal models have provided evidence for the dysregulation of specific neurochemical mechanisms in specific brain reward and stress circuits that provide the negative motivational state that drives addiction. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic drug ingestion with genetic vulnerability, but also provides the key by which to translate advances in animal studies to the human condition.

Brain-Stimulation Reward, Morphine-Induced Oral Stereotypy, and Sensitization: Implications for Abuse
Conan Kornetsky, Ph.D.

The development of the brain-stimulation reward for the study of the rewarding effects of drugs and the extent that it is related to sensitization of morphine-induced oral stereotypy will be briefly reviewed.

Evidence for protracted changes in brain and behavior, including results in aged rats, and the relevance of these models and findings for understanding mechanisms of abuse and relapse to opiate use will be presented.

Social Experiences: Amines and Peptides in the Mesocorticolimbic System
Klaus A. Miczek, Ph.D.

Salient social experiences trigger immediate early gene expression that is large, long-lasting, restricted to cells in the core areas of the neuroaxis, and critical to the fundamental processes of neuroadaptation. These biologically significant stressors activate cells in the endogenous aminergic and peptidergic systems leading ultimately to sensitization as well as tolerance. Several lines of evidence support the hypothesis that this cascade of cellular events is the basis for neural dysregulation leading to out-of-control drug taking. Examples from our ongoing work on the neural circuits for social stress and those mediating intensely rewarding activities such as compulsive cocaine administration point to considerable overlap between these neural circuits, and identifies targets for pharmacotherapeutic intervention in stress disorders and drug abuse.

Adaptations to Chronic Cocaine Exposure in a Nonhuman Primate Model
Linda Porrino, Ph.D.

Prolonged exposure to cocaine produces widespread dysregulation in dopamine systems. Using a nonhuman primate model of substance abuse, we have examined the temporal progression of the adaptations in dopamine transporters and receptors as experience with cocaine advances from initial to chronic stages of drug exposure. With more extended experience with cocaine, there is progressive involvement of broader aspects of striatal territory spreading beyond limbic domains into areas concerned with the processing of cognitive and motor information. The development of these adaptations reflects the intrinsic and extrinsic anatomical connections of the striatum and suggests that cocaine may have a widening influence on more aspects of behavior.

Amphetamine Neurotoxicity Research: Accomplishments and Remaining Challenges
G.A. Ricaurte, Ph.D.

The neurotoxic potential of methamphetamine toward brain dopamine neurons was discovered almost 3 decades ago. Since then, considerable progress has been made toward understanding the basic and clinical implications of this important discovery. This presentation will first highlight major research accomplishments to date, including the extension of methamphetamine findings to other amphetamine analogs and the recent demonstrations by several groups that findings of neuronal injury in methamphetamine-treated animals may generalize to human beings. Significant remaining challenges will then be identified. These include delineation of underlying mechanisms, understanding of species response differences, identification of functional consequences, and anticipation of possible tardive effects in humans previously exposed to neurotoxic amphetamine analogs.

Modeling the Addiction Process with Binge-Abstinence Patterns of Cocaine Self-Administration
David C.S. Roberts, Ph.D.

In most cocaine self-administration studies with rats, animals are given access to drug for only a few hours per day (typically 1-3 hours). Under these conditions, behavioral characteristics of cocaine self-administration do not change; levels and patterns of cocaine intake are stable and remain so over several months of testing. These characteristics have been extraordinarily useful in studies of drug reinforcement; however it appears that such limited access procedures do not model critical features of the addiction process such as a progression toward binge-abstinence patterns of drug use and an increased motivation to seek and use cocaine. Recently we have developed procedures that allow access to cocaine throughout the light/dark cycle for many weeks without toxicity. These include access to cocaine occurs during 10-minute trials that are initiated at regular intervals and presentation of 2 or 3 trials.

The Involvement of Cholinergic Neuronal Systems in Rodent Drug Self-Administration
James E. Smith, Ph.D.

Recent studies suggest the involvement of cholinergic neurons in the brain processes underlying reinforcement. The involvement of cholinergic neurons in opiate and cocaine reinforcement have been assessed by measuring the turnover rates of acetylcholine (ACh) in brain regions of rats intravenously self-administering morphine or cocaine and in yoked drug and yoked vehicle-infused controls. ACh turnover changes implicate the involvement of cholinergic neurons in the diagonal band-preoptic region, the medial septum, and several brainstem nuclei and interneurons in the nucleus accumbens, caudate-putamen, and ventral pallidum in the processes underlying self-administration. The role of ACh-releasing neurons in the diagonal band, ventral pallidum, and nucleus accumbens have been further investigated using a selective cholinergic neurotoxin to remove these cells and assess effects upon cocaine self-administration. These data support the involvement of cholinergic neurons in the ventral pallidum and diagonal band in the processes that underlie cocaine self-administration. The identified cholinergic neuronal systems may have a broader role in the brain processes for natural reinforcers (i.e. food, water, etc.) since drugs of abuse are believed to produce reinforcing effects through these systems.

Drug Abuse Genetics: Monoamines and Beyond
George R. Uhl, M.D., Ph.D.

My talk will begin with monoamine-based thinking about the molecular and molecular genetic bases of acute stimulant reward. I will then describe current remarkably convergent data that support influences of common, polygenic human allelic variants on human addiction vulnerability. I will discuss an emerging picture: Studying these variants may well take us far beyond catecholamine brain mechanisms and acute drug reward and may move us toward improved understanding of both drug pharmacodynamics and the learning-like processes that underlie much of addiction.

Sensitization of Midbrain Dopamine Neuron Reactivity and the Self-Administration of Psychomotor Stimulant Drugs
Paul Vezina, Ph.D.

Evidence will be presented showing that manipulations that produce sensitization of nucleus accumbens dopamine overflow enhance the pursuit and self-administration of psychomotor stimulant drugs. Procedures known to prevent the induction of this sensitization also prevent the facilitation of drug-taking. Finally, manipulations that increase nucleus accumbens dopamine overflow acutely, but fail to produce sensitization of this effect are not associated with the subsequent enhancement of self-administration. These results indicate a direct relationship between the sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of psychomotor stimulant drugs.

Brain Reward Circuitry and Addiction
Roy Wise, Ph.D.

Interest in the brain mechanisms of addiction was sparked by the discovery that rats will work for direct electrical stimulation of reward circuitry in the brain. Following the report that the behavior of rats working for intravenous amphetamine paralleled that of rats working for hypothalamic brain stimulation, cross-fertilization between behavioral pharmacologists and physiological psychologists was fostered at NIDA. Parallel studies of the two rewards led to the identification of brain dopamine as a central transmitter of reward-related messages, and subsequent characterization of drug-reward circuitry has focused on the mesolimbic dopamine system and its afferents and efferents.