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Dopamine Receptors and Transporters: Function, Imaging and Clinical Implication

2nd Edition, January 31, 2003

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ISBN: 978-0-8247-0854-2
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Product Details:

  • Revision: 2nd Edition, January 31, 2003
  • Published Date: January 31, 2003
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 662
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:

Preface

"From bench-to-bedside" is a dream that is central to scientists and clinicians alike. A simple dream finally! Nothing less than to investigate the basic biology of systems, to correlate them to the understanding of diseases, and to begin using them to manage or cure those diseases. Yet, only a few such dreams are fulfilled. Due to the tremendous advancements achieved by countless dedicated men and women working diligently this past decade in the field of dopamine receptors and transporters, we have now come closer to fulfilling this dream. While much remains to be done on benches in laboratories all over the world, we are now able to begin the clinical applications in the diagnosis and treatment of numerous dopamine-linked diseases. These diseases include schizophrenia, Parkinson's disease, movement disorders, multiple-system atrophy, obsessivecompulsive disorders and Gilles de la Tourette's syndrome, attention hyperactivity disorder, drug addiction, and alcohol abuse, to name a few.

The purpose of this book is to bring together information on both the basic and clinical advances in the field of dopamine systems. It is intended to be a reference for clinicians, scientists, and undergraduate and graduate students who want to learn more about what is arguably the most important neurotransmitter in the brain, as well as to provide information to established scientists outside their area of expertise. With over 90,000 scientific papers on dopamine published to date, we have tried to present a thorough and comprehensive overview of the field, with the hope that this book will inspire others to join us in our "bench-to-bedside" efforts.

Shortly before the first edition of this book was published in 1994, dopamine was identified as a neurotransmitter and a major player in the pathophysiology of human diseases such as Parkinson's disease and schizophrenia. At that time, the only possible approaches were neuroanatomy with histochemical techniques, analytical chemistry of the transmitter and its metabolites, and pharmacology of the receptors and transporters. In particular, dopamine receptors were thought of as basically operational entities necessary to account for dopamine action and its quantification, based on the effects of agonists and antagonists. Pharmacology of dopamine responses led to the definition of two classes of dopamine receptors, D1 and D2, but the events between ligand binding and measured effects were considered to be a "black box." The breakthrough achievement was the molecular cloning of D2 dopamine receptors, followed rapidly by the cloning of other dopamine receptor subtypes: D1, D3, D4, and D5. The advances were only the tip of an iceberg of dynamically interacting molecules, and soon new concepts about ligand binding and regulation of either signal transduction or neurotransmitter levels inside and outside neurons were proposed, analyzed, and confirmed.

It was quickly determined that D1 and D5 dopamine receptors share many of the same physiological and pharmacological features, in addition to being localized in the same regions of the brain. Similarly too, it became known that the D2 family of receptors-D2, D3, and D4-shared many overlapping properties and functions, as a legacy of their common ancestry. But perhaps most surprising was the finding that there are also commonalities between D1 and D2 families of receptors and that, in any event, the subtypes of these families interact with one another to modulate the functional activities of each other. This, in particular, negated the previously accepted sorting of dopamine receptors into two neat categories-D1 and D2-and it soon became apparent that life, as expressed by (dopamine receptors), was not quite so simple. With the development of selective pharmacological compounds came the ability to microdissect the signal transduction pathways linked to the individual receptors. And once again, preconceived notions were replaced by the growing awareness that many of these receptors modulate the same pathways, sometimes synergistically and sometimes in an opposing manner, due to their contribution of large molecular assemblies in the compartmentalized space of the neuron. In this book we show how some very pioneering work by many scientists has converged to elucidate the intricacies underlying these many systems. And in every chapter, the incompleteness of this research is highlighted.

Similar progress and microdissection of the dopamine transporter also took place during this time. We learned that this protein is responsible for the uptake of neurotoxins that cause Parkinson's disease and that this protein is involved in cocaine and amphetamine addiction. But most of all we learned that the dopamine transporter is absolutely essential for removal and recycling of dopamine from synapses. And even now, we are learning how the dopamine transporter is regulated by interaction with a dynamic network of compartmentalized proteins to maintain dopamine homeostasis, both intracellularly and extracellularly.

As stated in many places in this book, the neuromodulatory role of dopamine is of tremendous importance in shaping the brain connections and the plasticity of neuronal responses, throughout life, from embryonic stages to the elderly. Thus, normal interactions of dopamine systems will obviously depend on the integrity of the other neuronal systems they modulate. It becomes easier to understand why and how multiple, genetically determined variations in brain organization and physiology-even if they are essentially compensated by a high redundancy in brain construction-may lead to pathological states when an individual's life becomes highly challenging, leading to a strong imbalance in the effect of dopamine, in response to novelty for example. It is the reason why developing animal models in which a single gene has been invalidated or modified is so important to help us understand the nature of pathological processes. The idea here is that no more than one gene determines one phenotype. However, one gene deficit may lead to several different responses, depending on the way the brain has been shaped by the experience, and more especially by dopamine systems, and on the kind of challenging situations the individual may be facing.

A large part of this book is dedicated to imaging studies of dopamine systems in humans. These sophisticated techniques, although still lacking precise anatomical resolution, allow for assessing links between activation of dopamine systems and processing of affective, cognitive, sensorimotor inputs and programs. More importantly, they provide much needed information on the integration of dopamine action in a larger view of interconnected functional systems in the brain. In pathological states such as schizophrenia, the role of dopamine has been challenged but not dismissed. It simply appears, again and as ever, that dopamine does not operate alone in the brain, but, instead, interacts with executive neuronal systems. Together with animal models, brain imaging techniques show dopamine as an entry point and final common pathway of more complex and general alterations of brain functions. The dopamine mesencephalotelencephalic system, and its various components, are differentially implicated in pathological states that have in common alteration of emotional vibrancy and perturbed motivations. In contrast, depending on the pathological conditions, morphological or functional changes of dopamine systems are accompanied by variable alterations, either anatomical or metabolic, in the dorsal and ventral striatum, in the anterior and mediodorsal thalamic nuclei, in the prefrontal cortex, or even in the hippocampus, highlighting the numerous and powerful adaptations the brain undergoes after the onset of a pathological process. Brain imaging studies were instrumental to demonstrate involvement of presynaptic regulation or postsynaptic sensitization in schizophrenic states or drug addiction.

The fundamental concept of neuromodulation is more than ever very powerful in accounting for the role of dopamine in connecting fundamental built-in or learned behavioral skills in the day-to-day experience of subjects. There is some irony but great scientific beauty in the fact that dopamine not only encompasses general terms (those accessible only to experimental scientists) but is also extremely crucial to the most individually unique aspects of life (the personal history of the person).

Finally, this book is dedicated to the editor of the first edition, Dr. Hyman (Chaim) Niznik, for his work, his personality, his inspiration, and his numerous contributions to the field of dopamine receptors and transporters. Chaim Niznik began his research on dopamine receptors in the mid-1980s and had published over 100 scientific articles on his research before his untimely death at the age of 43. He was the first to develop specific photoaffinity ligands that distinguished the dopamine receptors and to clone the D1, D4, and D5 dopamine receptors. Just prior to his death, he made the very important discovery that dopamine receptors interact with receptors that modulate ion channels, thus showing how GPCR-coupled systems interact with other seemingly unrelated systems, a discovery that has tremendous implications for neurophysiology. After his death, two other extremely important papers on his work were published: one was on the modulation of dopamine transporters by á-synuclein, with important consequences for the genesis of Parkinson's disease. The other paper showed how D1 dopamine receptors interacted with NMDA receptors. Thus, it would not be an overstatement to say that Chaim was truly far ahead of others, in his concepts, innovations, and dreams. And those of us privileged to have known him hope that we can continue to fulfill those dreams and turn them into reality.

As a person, he defied the stereotypical image of a scientist, with his infectious enthusiasm, terrific sense of humor, and love of heavy-metal music. His active mind, his ability to foresee and predict scientific events a whole decade before others, and, most important, his adamant refusal to believe that he was "God's gift to science" is what endeared him to his colleagues and collaborators. In many ways, this book is his legacy. As he once said, "We do what we think is good science. And ultimately, it is for the world to judge if we have wasted our life or not." As all of us who work in the field can attest, his was not wasted.